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Shyam M, Bm O, Srirangan P, N N, Sabina EP. Targeted miRNA Delivery in Epilepsy: Mechanisms, Advances, and Therapeutic Potential. Mol Biol Rep 2025; 52:368. [PMID: 40192852 DOI: 10.1007/s11033-025-10436-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 03/11/2025] [Indexed: 04/23/2025]
Abstract
Epilepsy, a neurological disorder characterized by recurrent seizures, presents significant therapeutic challenges, with roughly 30% of individuals demonstrating resistance to antiepileptic drugs. Drug-resistant epilepsy diminishes patients' quality of life and underscores the critical need for innovative therapeutic approaches. MicroRNAs, small non-coding RNA molecules, have emerged as key regulators in the pathogenesis of epilepsy, influencing neuronal excitability, synaptic plasticity, and neuroinflammatory processes. By targeting multiple genes and pathways involved in epileptogenesis, miRNAs offer promising opportunities for precision medicine. This review explores the dual roles of specific miRNAs in epilepsy, acting as both promoters and inhibitors of pathogenic pathways, and highlights recent advancements in miRNA-based therapeutic delivery systems. State-of-the-art approaches, including lipid nanoparticles, viral vectors, and exosome-based systems, are being developed to address challenges such as blood-brain barrier penetration, targeted delivery, and minimizing systemic side effects. These advancements lay the groundwork for more effective and personalized treatment strategies.
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Affiliation(s)
- Mukul Shyam
- Department of Biotechnology, School of Biosciences and Technology, VIT University, Tamil Nadu, Vellore, 632014, India
| | - Oveyaa Bm
- Department of Biotechnology, School of Biosciences and Technology, VIT University, Tamil Nadu, Vellore, 632014, India
| | - Prathap Srirangan
- Department of Biotechnology, School of Biosciences and Technology, VIT University, Tamil Nadu, Vellore, 632014, India
| | - Nivedita N
- Department of Biotechnology, School of Biosciences and Technology, VIT University, Tamil Nadu, Vellore, 632014, India
| | - Evan Prince Sabina
- Department of Biotechnology, School of Biosciences and Technology, VIT University, Tamil Nadu, Vellore, 632014, India.
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Samões R, Cavalheiro A, Santos C, Lopes J, Teixeira C, Tavares MM, Carvalho C, Lemos C, E Costa PP, Cavaco S, Chaves J, Leal B. MicroRNAs as potential biomarkers of response to modified Atkins diet in treatment of adults with drug-resistant epilepsy: A proof-of-concept study. Epilepsy Res 2024; 208:107478. [PMID: 39536682 DOI: 10.1016/j.eplepsyres.2024.107478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 11/01/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Accurate predictors of response to modified Atkins diet (MAD) are needed. MicroRNAs are potential biomarkers in epilepsy. This study aimed to explore the value of circulating miR-146a, miR-155, miR-22, miR-21 and miR-134 levels in predicting response to MAD. METHODS Patients who completed 3 months of MAD were selected from a prospective cohort of adults with DRE followed in a specialized MAD outpatient clinic. Patients were classified as responders if any reduction in seizure frequency at follow-up, calculated through seizure-calendars). The >50 % seizure reduction cut-off was also explored. Qualitative benefits in seizures and cognition were analysed. Blood samples were collected prior to initiate MAD and microRNAs were quantified by qRT-PCR. RESULTS Thirty-nine patients were included (56 %males, mean age=33.1±8.5yo, 62 %focal epilepsies, 59 %structural aetiology): 20(51 %) were responders [mean reduction in seizure frequency=54 %(17-100 %); 10 had ≥50 % reduction]; 25(64 %) reported qualitative benefit in seizures and 21(54 %) reported cognitive benefits. At pre-treatment baseline, a panel combining serum levels of all studied microRNAs predicted seizure reduction (AUC=0.839, p<0.0001), qualitative benefit in seizures (AUC=0.683, p=0.048) and in cognition (AUC=0.751, p<0.01) at 3months. miR-146a was the only significant microRNA when evaluated in isolation. There was no statistical correlation in the biomarkers when a ≥50 % seizure reduction was compared to <50 %. CONCLUSIONS A panel combining pre-treatment serum levels of miR-146a, miR-155, miR-134, miR-21 and miR-22 predicted any reduction in seizures with MAD in adults with DRE at 3months. This panel may be a promising biomarker and a useful tool in the selection of patients.
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Affiliation(s)
- Raquel Samões
- Neurology Department, Centro Hospitalar Universitário de Santo António, ULS Santo António, Porto, Portugal; Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Biomedical Sciences Institute - University of Porto, Porto, Portugal; Laboratory for Integrative and Translational Research in Population Health (ITR), Porto, Portugal.
| | - Ana Cavalheiro
- Nutrition Service, Centro Hospitalar Universitário do Porto, ULS Santo António, Porto, Portugal
| | - Cristina Santos
- Immunogenetics Laboratory, Abel Salazar Biomedical Sciences Institute - University of Porto, Porto, Portugal
| | - Joana Lopes
- Neurology Department, Centro Hospitalar Universitário de Santo António, ULS Santo António, Porto, Portugal
| | - Catarina Teixeira
- Neurology Department, Centro Hospitalar Universitário de Santo António, ULS Santo António, Porto, Portugal
| | - Maria Manuel Tavares
- Nutrition Service, Centro Hospitalar Universitário do Porto, ULS Santo António, Porto, Portugal
| | - Cláudia Carvalho
- Immunogenetics Laboratory, Abel Salazar Biomedical Sciences Institute - University of Porto, Porto, Portugal
| | - Carolina Lemos
- ICBAS, School of Medicine and Biomedical Sciences - University of Porto, Porto, Portugal; UnIGENe, IBMC - Instituto de Biologia Celular Molecular, Portugal; i3S‑Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Paulo Pinho E Costa
- Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Biomedical Sciences Institute - University of Porto, Porto, Portugal; Laboratory for Integrative and Translational Research in Population Health (ITR), Porto, Portugal; Immunogenetics Laboratory, Abel Salazar Biomedical Sciences Institute - University of Porto, Porto, Portugal; Genetics Department, Instituto Nacional de Saúde Dr. Ricardo Jorge, Porto, Portugal
| | - Sara Cavaco
- Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Biomedical Sciences Institute - University of Porto, Porto, Portugal; Laboratory for Integrative and Translational Research in Population Health (ITR), Porto, Portugal; Neuropsychology Service, Centro Hospitalar Universitário de Santo António, ULS Santo António, Porto, Portugal
| | - João Chaves
- Neurology Department, Centro Hospitalar Universitário de Santo António, ULS Santo António, Porto, Portugal; Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Biomedical Sciences Institute - University of Porto, Porto, Portugal; Laboratory for Integrative and Translational Research in Population Health (ITR), Porto, Portugal
| | - Bárbara Leal
- Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Biomedical Sciences Institute - University of Porto, Porto, Portugal; Laboratory for Integrative and Translational Research in Population Health (ITR), Porto, Portugal; Immunogenetics Laboratory, Abel Salazar Biomedical Sciences Institute - University of Porto, Porto, Portugal
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Vahidi Z, Saghi E, Mahmoudi M, RezaieYazdi Z, Esmaeili SA, Zemorshidi F, Samadi M, Rastin M. Lactobacillus rhamnosus and Lactobacillus delbrueckii Ameliorate the Expression of miR-125a and miR-146a in Systemic Lupus Erythematosus Patients. Appl Biochem Biotechnol 2024; 196:6330-6341. [PMID: 38351428 DOI: 10.1007/s12010-023-04827-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2023] [Indexed: 11/29/2024]
Abstract
The microRNAs are non-coding RNA molecules involved in physiological and pathological processes, causing autoimmune diseases such as systemic lupus erythematosus (SLE). Probiotics are living microorganisms that possess beneficial effects on the host immune system and modulate it. The effect of Lactobacillus rhamnosus and Lactobacillus delbrueckii on the expression of miR-125a and miR-146a was studied in peripheral blood mononuclear cells (PBMCs) from newly diagnosed lupus patients in this in vitro study. During this study, 20 recently diagnosed SLE patients and 20 healthy individuals participated. Ficoll method was used to isolate the PBMCs from whole blood, which were cultured for 48 h with Lactobacillus rhamnosus and Lactobacillus delbrueckii. In the next step, total RNA containing microRNA was extracted. cDNA was synthesized for miR-125a and miR-146a genes and analyzed by real-time PCR. Results were presented as fold changes. As compared to healthy controls, SLE patients expressed lower levels of miR-125a and miR-146a. PBMCs treated with Lactobacillus rhamnosus, Lactobacillus delbrueckii, or both probiotics had significantly higher levels of miR-125a and miR-146a compared to the untreated group. Treatment of PBMCs with both L. rhamnosus and L. delbrueckii upregulated the expression of miR-125a and miR-146a in treated cells compared with untreated cells in SLE patients (p = 0.02, p = 0.001). Lactobacillus rhamnosus and Lactobacillus delbrueckii modify lupus patients' immune responses and disease effects by regulating miR-125a and miR-146a.
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Affiliation(s)
- Zohreh Vahidi
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Effat Saghi
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Mahmoudi
- Immunology Departments, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra RezaieYazdi
- Rheumatic Diseases Research Center, Ghaem Hospital, Internal Medicine Section, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed-Alireza Esmaeili
- Immunology Departments, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fariba Zemorshidi
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Morteza Samadi
- Department of Immunology, Faculty of Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Maryam Rastin
- Immunology Departments, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Khemka N, Morris G, Kazemzadeh L, Costard LS, Neubert V, Bauer S, Rosenow F, Venø MT, Kjems J, Henshall DC, Prehn JHM, Connolly NMC. Integrative network analysis of miRNA-mRNA expression profiles during epileptogenesis in rats reveals therapeutic targets after emergence of first spontaneous seizure. Sci Rep 2024; 14:15313. [PMID: 38961125 PMCID: PMC11222454 DOI: 10.1038/s41598-024-66117-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 06/27/2024] [Indexed: 07/05/2024] Open
Abstract
Epileptogenesis is the process by which a normal brain becomes hyperexcitable and capable of generating spontaneous recurrent seizures. The extensive dysregulation of gene expression associated with epileptogenesis is shaped, in part, by microRNAs (miRNAs) - short, non-coding RNAs that negatively regulate protein levels. Functional miRNA-mediated regulation can, however, be difficult to elucidate due to the complexity of miRNA-mRNA interactions. Here, we integrated miRNA and mRNA expression profiles sampled over multiple time-points during and after epileptogenesis in rats, and applied bi-clustering and Bayesian modelling to construct temporal miRNA-mRNA-mRNA interaction networks. Network analysis and enrichment of network inference with sequence- and human disease-specific information identified key regulatory miRNAs with the strongest influence on the mRNA landscape, and miRNA-mRNA interactions closely associated with epileptogenesis and subsequent epilepsy. Our findings underscore the complexity of miRNA-mRNA regulation, can be used to prioritise miRNA targets in specific systems, and offer insights into key regulatory processes in epileptogenesis with therapeutic potential for further investigation.
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Affiliation(s)
- Niraj Khemka
- Centre for Systems Medicine & Dept. of Physiology & Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Gareth Morris
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- Neuroscience, Physiology and Pharmacology, University College London, London, UK
- Division of Neuroscience, University of Manchester, Manchester, UK
| | - Laleh Kazemzadeh
- Centre for Systems Medicine & Dept. of Physiology & Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Lara S Costard
- Epilepsy Center, Department of Neurology, Philipps University Marburg, Marburg, Germany
- Epilepsy Center Frankfurt Rhine-Main, Neurocenter, University Hospital Frankfurt and Center for Personalized Translational Epilepsy Research, Goethe-University, Frankfurt, Germany
| | - Valentin Neubert
- Epilepsy Center, Department of Neurology, Philipps University Marburg, Marburg, Germany
- Epilepsy Center Frankfurt Rhine-Main, Neurocenter, University Hospital Frankfurt and Center for Personalized Translational Epilepsy Research, Goethe-University, Frankfurt, Germany
| | - Sebastian Bauer
- Epilepsy Center, Department of Neurology, Philipps University Marburg, Marburg, Germany
- Epilepsy Center Frankfurt Rhine-Main, Neurocenter, University Hospital Frankfurt and Center for Personalized Translational Epilepsy Research, Goethe-University, Frankfurt, Germany
| | - Felix Rosenow
- Epilepsy Center, Department of Neurology, Philipps University Marburg, Marburg, Germany
- Epilepsy Center Frankfurt Rhine-Main, Neurocenter, University Hospital Frankfurt and Center for Personalized Translational Epilepsy Research, Goethe-University, Frankfurt, Germany
| | - Morten T Venø
- Interdisciplinary Nanoscience Center, Dept. of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
- Omiics ApS, Aarhus, Denmark
| | - Jørgen Kjems
- Interdisciplinary Nanoscience Center, Dept. of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - David C Henshall
- Centre for Systems Medicine & Dept. of Physiology & Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Jochen H M Prehn
- Centre for Systems Medicine & Dept. of Physiology & Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
| | - Niamh M C Connolly
- Centre for Systems Medicine & Dept. of Physiology & Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
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Ildarabadi A, Mir Mohammad Ali SN, Rahmani F, Mosavari N, Pourbakhtyaran E, Rezaei N. Inflammation and oxidative stress in epileptic children: from molecular mechanisms to clinical application of ketogenic diet. Rev Neurosci 2024; 35:473-488. [PMID: 38347675 DOI: 10.1515/revneuro-2023-0128] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 12/18/2023] [Indexed: 06/02/2024]
Abstract
Childhood epilepsy affects up to 1 % of children. It has been shown that 30 % of patients are resistant to drug treatments, making further investigation of other potential treatment strategies necessary. One such approach is the ketogenic diet (KD) showing promising results and potential benefits beyond the use of current antiepileptic drugs. This study aims to investigate the effects of KD on inflammation and oxidative stress, as one of the main suggested mechanisms of neuroprotection, in children with epilepsy. This narrative review was conducted using the Medline and Google Scholar databases, and by searching epilepsy, drug-resistant epilepsy, child, children, ketogenic, ketogenic diet, diet, ketogenic, keto, ketone bodies (BHB), PUFA, gut microbiota, inflammation, inflammation mediators, neurogenic inflammation, neuroinflammation, inflammatory marker, adenosine modulation, mitochondrial function, MTOR pathway, Nrf2 pathway, mitochondrial dysfunction, PPARɣ, oxidative stress, ROS/RNS, and stress oxidative as keywords. Compelling evidence underscores inflammation and oxidative stress as pivotal factors in epilepsy, even in cases with genetic origins. The ketogenic diet effectively addresses these factors by reducing ROS and RNS, enhancing antioxidant defenses, improving mitochondrial function, and regulating inflammatory genes. Additionally, KD curbs pro-inflammatory cytokine and chemokine production by dampening NF-κB activation, inhibiting the NLRP3 inflammasome, increasing brain adenosine levels, mTOR pathway inhibition, upregulating PPARɣ expression, and promoting a healthy gut microbiota while emphasizing the consumption of healthy fats. KD could be considered a promising therapeutic intervention in patients with epilepsy particularly in drug-resistant epilepsy cases, due to its targeted approach addressing oxidative stress and inflammatory mechanisms.
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Affiliation(s)
- Azam Ildarabadi
- Department of Nutrition Science, Science and Research Branch, Faculty of Medical Science and Technology, Islamic Azad University, Shodada Hesarak Blvd, Tehran 1477893855, Iran
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Dr. Qarib St, Tehran 1419733151, Iran
| | - Seyedeh Nooshan Mir Mohammad Ali
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Dr. Qarib St, Tehran 1419733151, Iran
- Department of Food, Nutrition, Dietetics and Health, Kansas State University, Manhattan, KS 66502, USA
| | - Fatemeh Rahmani
- Department of Nutrition Science, Science and Research Branch, Faculty of Medical Science and Technology, Islamic Azad University, Shodada Hesarak Blvd, Tehran 1477893855, Iran
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Dr. Qarib St, Tehran 1419733151, Iran
| | - Narjes Mosavari
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Dr. Qarib St, Tehran 1419733151, Iran
| | - Elham Pourbakhtyaran
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Dr. Qarib St, Tehran 1419733151, Iran
- Department of Pediatric Neurology, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Tehran 1419733151, Iran
| | - Nima Rezaei
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Dr. Qarib St, Tehran 1419733151, Iran
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center Hospital, Tehran University of Medical Sciences, Dr. Qarib St, Tehran 1419733151, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Science, Pour Sina St, Tehran 1461884513, Iran
- Research Center for Immunodeficiencies, Children's Medical Center Hospital, Dr. Qarib St, Keshavarz Blvd, Tehran 14194, Iran
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Pant K, Sharma A, Menon SV, Ali H, Hassan Almalki W, Kaur M, Deorari M, Kazmi I, Mahajan S, Kalra H, Alzarea SI. Exploring ncRNAs in epilepsy: From oxidative stress regulation to therapy. Brain Res 2024; 1841:149089. [PMID: 38880410 DOI: 10.1016/j.brainres.2024.149089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 06/10/2024] [Accepted: 06/13/2024] [Indexed: 06/18/2024]
Abstract
Epilepsy is a prevalent neurological illness which is linked with high worldwide burdens. Oxidative stress (OS) is recognized to be among the contributors that trigger the advancement of epilepsy, affecting neuronal excitability and synaptic transmission. Various types of non-coding RNAs (ncRNAs) are known to serve vital functions in many disease mechanisms, including epilepsy. The current review sought to understand better the mechanisms through which these ncRNAs regulate epilepsy's OS-related pathways. We investigated the functions of microRNAs in controlling gene expression at the post-translatory stage and their involvement in OS and neuroinflammation. We also looked at the different regulatory roles of long ncRNAs, including molecular scaffolding, enhancer, and transcriptional activator, during OS. Circular RNAs and their capability to act as miRNA decoys and their consequential impact on epilepsy development were also explored. Our review aimed to improve the current understanding of novel therapies for epilepsy based on the role of ncRNAs in OS pathways. We also demonstrated the roles of ncRNAs in epilepsy treatment and diagnosis, explaining that these molecules play vital roles that could be used in therapy as biomarkers.
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Affiliation(s)
- Kumud Pant
- Graphic Era (Deemed to be University), Clement Town Dehradun, 248002, India; Graphic Era Hill University Clement Town Dehradun, 248002, India
| | - Aanchal Sharma
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Jhanjheri, Mohali 140307, Punjab, India
| | - Soumya V Menon
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, Karnataka 560069, India; Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India; Department of Pharmacology, Kyrgyz State Medical College, Bishkek, Kyrgyzstan.
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mandeep Kaur
- Department of Sciences, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Mahamedha Deorari
- School of Basic & Applied Sciences, Shobhit University, Gangoh, Uttar Pradesh-247341, India; Department of Health & Allied Sciences, Arka Jain University, Jamshedpur, Jharkhand- 831001, India
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, 21589, Jeddah, Saudi Arabia
| | - Shriya Mahajan
- Centre of Research Impact and Outcome, Chitkara University, Rajpura 140417, Punjab, India
| | - Hitesh Kalra
- Chitkara Centre for Research and Development, Chitkara University, Himachal Pradesh 174103, India
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, 72341, Sakaka, Aljouf, Saudi Arabia
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Buainain RP, Sodré AR, dos Santos JS, Takazaki KAG, Queiroz LDS, de Oliveira CTP, de Aguiar PHP, Marson FAL, Ortega MM. Single-Base Gene Variants in MIR-146A and SCN1A Genes Related to the Epileptogenic Process in Drug-Responsive and Drug-Resistant Temporal Lobe Epilepsy-A Preliminary Study in a Brazilian Cohort Sample. Int J Mol Sci 2024; 25:6005. [PMID: 38892194 PMCID: PMC11172889 DOI: 10.3390/ijms25116005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 05/22/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
The drug-resistant temporal lobe epilepsy (TLE) has recently been associated with single nucleotide variants (SNVs) in microRNA(miR)-146a (MIR-146A) (rs2910164) and Sodium Voltage-Gated Channel Alpha Subunit 1 (SCN1A) (rs2298771 and rs3812718) genes. Moreover, no studies have shown an association between these SNVs and susceptibility to drug-resistant and drug-responsive TLE in Brazil. Thus, deoxyribonucleic acid (DNA) samples from 120 patients with TLE (55 drug-responsive and 65 drug-resistant) were evaluated by real-time polymerase chain reaction (RT-PCR). A total of 1171 healthy blood donor individuals from the Online Archive of Brazilian Mutations (ABraOM, from Portuguese Arquivo Brasileiro On-line de Mutações), a repository containing genomic variants of the Brazilian population, were added as a control population for the studied SNVs. MIR-146A and SCN1A relative expression was performed by quantitative RT-PCR (qRT-PCR). The statistical analysis protocol was performed using an alpha error of 0.05. TLE patient samples and ABraOM control samples were in Hardy-Weinberg equilibrium for all studied SNVs. For rs2910164, the frequencies of the homozygous genotype (CC) (15.00% vs. 9.65%) and C allele (37.80% vs. 29.97%) were superior in patients with TLE compared to controls with a higher risk for TLE disease [odds ratio (OR) = 1.89 (95% confidence interval (95%CI) = 1.06-3.37); OR = 1.38 (95%CI = 1.04-1.82), respectively]. Drug-responsive patients also presented higher frequencies of the CC genotype [21.81% vs. 9.65%; OR = 2.58 (95%CI = 1.25-5.30)] and C allele [39.09% vs. 29.97%; OR = 1.50 (95%CI = 1.01-2.22)] compared to controls. For rs2298771, the frequency of the heterozygous genotype (AG) (51.67% vs. 40.40%) was superior in patients with TLE compared to controls with a higher risk for TLE disease [OR = 2.42 (95%CI = 1.08-5.41)]. Drug-resistant patients presented a higher AG frequency [56.92% vs. 40.40%; OR = 3.36 (95%CI = 1.04-17.30)] compared to the control group. For rs3812718, the prevalence of genotypes and alleles were similar in both studied groups. The MIR-146A relative expression level was lower in drug-resistant compared to drug-responsive patients for GC (1.6 vs. 0.1, p-value = 0.049) and CC (1.8 vs. 0.6, p-value = 0.039). Also, the SCN1A relative expression levels in samples from TLE patients were significantly higher in AG [2.09 vs. 1.10, p-value = 0.038] and GG (3.19 vs. 1.10, p-value < 0.001) compared to the AA genotype. In conclusion, the rs2910164-CC and rs2298771-AG genotypes are exerting significant risk influence, respectively, on responsive disease and resistant disease, probably due to an upregulated nuclear factor kappa B (NF-kB) and SCN1A loss of function.
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Affiliation(s)
- Renata Parissi Buainain
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University, Bragança Paulista 12916-900, SP, Brazil or (F.A.L.M.)
- Laboratory of Molecular Biology and Genetics, São Francisco University, Bragança Paulista 12916-900, SP, Brazil
| | - André Rodrigues Sodré
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University, Bragança Paulista 12916-900, SP, Brazil or (F.A.L.M.)
- Laboratory of Molecular Biology and Genetics, São Francisco University, Bragança Paulista 12916-900, SP, Brazil
| | - Jéssica Silva dos Santos
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University, Bragança Paulista 12916-900, SP, Brazil or (F.A.L.M.)
- Laboratory of Molecular Biology and Genetics, São Francisco University, Bragança Paulista 12916-900, SP, Brazil
| | - Karen Antonia Girotto Takazaki
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University, Bragança Paulista 12916-900, SP, Brazil or (F.A.L.M.)
- Laboratory of Molecular Biology and Genetics, São Francisco University, Bragança Paulista 12916-900, SP, Brazil
| | - Luciano de Souza Queiroz
- Department of Pathology, Faculty of Medical Science, University of Campinas, Campinas 13083-970, SP, Brazil;
| | - Carlos Tadeu Parisi de Oliveira
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University, Bragança Paulista 12916-900, SP, Brazil or (F.A.L.M.)
- Laboratory of Molecular Biology and Genetics, São Francisco University, Bragança Paulista 12916-900, SP, Brazil
- São Francisco University Hospital, São Francisco University, Bragança Paulista 20210-030, SP, Brazil
| | - Paulo Henrique Pires de Aguiar
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University, Bragança Paulista 12916-900, SP, Brazil or (F.A.L.M.)
- Laboratory of Molecular Biology and Genetics, São Francisco University, Bragança Paulista 12916-900, SP, Brazil
- Department of Neurosurgery, Hospital Santa Paula, São Paulo 04556-100, SP, Brazil
| | - Fernando Augusto Lima Marson
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University, Bragança Paulista 12916-900, SP, Brazil or (F.A.L.M.)
- Laboratory of Molecular Biology and Genetics, São Francisco University, Bragança Paulista 12916-900, SP, Brazil
| | - Manoela Marques Ortega
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University, Bragança Paulista 12916-900, SP, Brazil or (F.A.L.M.)
- Laboratory of Molecular Biology and Genetics, São Francisco University, Bragança Paulista 12916-900, SP, Brazil
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8
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Yang M, Li Y, Liu X, Zou S, Lei L, Zou Q, Zhang Y, Fang Y, Chen S, Zhou L. Autophagy-related genes in mesial temporal lobe epilepsy: an integrated bioinformatics analysis. ACTA EPILEPTOLOGICA 2024; 6:16. [PMID: 40217519 PMCID: PMC11960276 DOI: 10.1186/s42494-024-00160-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 03/27/2024] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Autophagy plays essential roles in the development and pathogenesis of mesial temporal lobe epilepsy (mTLE). In this research, we aim to identify and validate the autophagy-related genes associated with mTLE through bioinformatics analysis and experimental validations. METHODS We obtained the dataset GSE143272 and high-throughput sequencing results of mTLE from public databases. Potential differentially expressed autophagy-related genes related to mTLE were identified using R software. Subsequently, genomes pathway enrichment analysis, protein-protein interactions (PPIs), and the gene ontology (GO) enrichment were performed for the selected autophagy-related genes. The mRNA expression profiles of hub genes were then used to establish a least absolute shrinkage and selection operator (LASSO) model. Finally, seven hub candidate autophagy-related genes were confirmed in hippocampus using the lithium-pilocarpine chronic epilepsy model. RESULTS A total of 40 differential expression genes (DEGs) among the core autophagy-related genes were identified. The analysis results of PPI revealed that interactions among these DEGs. KEGG pathway and GO analysis of selected candidate autophagy-related genes indicated that those enriched terms mainly focused on macroautophagy, regulation of autophagy, cellular response to extracellular stimulus and mitochondrion disassembly. The results suggested that SQSTM1, VEGFA, BNIP and WIPI2 were consistent with the bioinformatics analysis. The expression levels of SQSTM1 and VEGFA in epilepsy model samples were significantly higher than those in normal control, while BNIP and WIPI2 expression levels were notably decreased. The final hub gene-based LASSO regression model accurately predicted the occurrence of epilepsy (AUC = 0.88). CONCLUSIONS Through bioinformatics analysis of public data, we identified 40 candidate autophagy-related genes associated with mTLE. SQSTM1, VEGFA, BNIP and WIPI2 may play significant roles in autophagy, influencing the onset and development of mTLE by regulating autophagy pathway. These findings deepen our understanding of mTLE, and may serve as sensitive and valuable indicators for the prognosis and diagnosis of this condition.
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Affiliation(s)
- Man Yang
- Department of Neurology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, Guangdong Province, China
| | - Yinchao Li
- Department of Neurology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, Guangdong Province, China
| | - Xianyue Liu
- Department of Neurology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, Guangdong Province, China
| | - Shangnan Zou
- Department of Neurology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, Guangdong Province, China
| | - Lei Lei
- Department of Neurology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, Guangdong Province, China
| | - Qihang Zou
- Department of Neurology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, Guangdong Province, China
| | - Yaqian Zhang
- Department of Neurology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, Guangdong Province, China
| | - Yubao Fang
- Department of Neurology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, Guangdong Province, China
| | - Shuda Chen
- Department of Neurology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, Guangdong Province, China.
| | - Liemin Zhou
- Department of Neurology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, Guangdong Province, China.
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9
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Jeelani M. miRNAs in epilepsy: A review from molecular signatures to therapeutic intervention. Int J Biol Macromol 2024; 263:130468. [PMID: 38417757 DOI: 10.1016/j.ijbiomac.2024.130468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/17/2024] [Accepted: 02/24/2024] [Indexed: 03/01/2024]
Abstract
Epilepsy is a medical disorder marked by sporadic seizures accompanied by alterations in consciousness. The molecular mechanisms responsible for epilepsy and the factors contributing to alterations in neuronal structure compromised apoptotic responses in neurons, and disturbances in regeneration pathways in glial cells remain unidentified. MicroRNAs (miRNAs) are short noncoding RNA that consist of a single strand. They typically contain 21 to 23 nucleotides. miRNAs participate in the process of RNA silencing and the regulation of gene expression after transcription by selectively binding to mRNA molecules that possess complementary sequences. The disruption of miRNA regulation has been associated with the development of epilepsy, and manipulating a single miRNA can impact various cellular processes, hence serving as a potent intervention approach. Despite existing obstacles in the delivery and safety of miRNA-based treatments, researchers are actively investigating the potential of miRNAs to operate as regulators of brain activity and as targets for treating and preventing epilepsy. Hence, the utilization of miRNA-based therapeutic intervention shows potential for future epilepsy management. The objective of our present investigation was to ascertain the involvement of miRNAs in the causation and advancement of epilepsy. Moreover, they have undergone scrutiny for their potential utilization in therapeutic intervention.
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Affiliation(s)
- Mohammed Jeelani
- Department of Physiology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
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10
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Guarnieri L, Amodio N, Bosco F, Carpi S, Tallarico M, Gallelli L, Rania V, Citraro R, Leo A, De Sarro G. Circulating miRNAs as Novel Clinical Biomarkers in Temporal Lobe Epilepsy. Noncoding RNA 2024; 10:18. [PMID: 38525737 PMCID: PMC10961783 DOI: 10.3390/ncrna10020018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 03/14/2024] [Accepted: 03/15/2024] [Indexed: 03/26/2024] Open
Abstract
Temporal lobe epilepsy (TLE) represents the most common form of refractory focal epilepsy. The identification of innovative clinical biomarkers capable of categorizing patients with TLE, allowing for improved treatment and outcomes, still represents an unmet need. Circulating microRNAs (c-miRNAs) are short non-coding RNAs detectable in body fluids, which play crucial roles in the regulation of gene expression. Their characteristics, including extracellular stability, detectability through non-invasive methods, and responsiveness to pathological changes and/or therapeutic interventions, make them promising candidate biomarkers in various disease settings. Recent research has investigated c-miRNAs in various bodily fluids, including serum, plasma, and cerebrospinal fluid, of TLE patients. Despite some discrepancies in methodologies, cohort composition, and normalization strategies, a common dysregulated signature of c-miRNAs has emerged across different studies, providing the basis for using c-miRNAs as novel biomarkers for TLE patient management.
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Affiliation(s)
- Lorenza Guarnieri
- Section of Pharmacology, Science of Health Department, School of Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (L.G.); (F.B.); (S.C.); (M.T.); (L.G.); (V.R.); (A.L.); (G.D.S.)
| | - Nicola Amodio
- Department of Experimental and Clinical Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Francesca Bosco
- Section of Pharmacology, Science of Health Department, School of Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (L.G.); (F.B.); (S.C.); (M.T.); (L.G.); (V.R.); (A.L.); (G.D.S.)
| | - Sara Carpi
- Section of Pharmacology, Science of Health Department, School of Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (L.G.); (F.B.); (S.C.); (M.T.); (L.G.); (V.R.); (A.L.); (G.D.S.)
| | - Martina Tallarico
- Section of Pharmacology, Science of Health Department, School of Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (L.G.); (F.B.); (S.C.); (M.T.); (L.G.); (V.R.); (A.L.); (G.D.S.)
| | - Luca Gallelli
- Section of Pharmacology, Science of Health Department, School of Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (L.G.); (F.B.); (S.C.); (M.T.); (L.G.); (V.R.); (A.L.); (G.D.S.)
- Research Center FAS@UMG, Department of Health Science, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Vincenzo Rania
- Section of Pharmacology, Science of Health Department, School of Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (L.G.); (F.B.); (S.C.); (M.T.); (L.G.); (V.R.); (A.L.); (G.D.S.)
| | - Rita Citraro
- Section of Pharmacology, Science of Health Department, School of Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (L.G.); (F.B.); (S.C.); (M.T.); (L.G.); (V.R.); (A.L.); (G.D.S.)
- Research Center FAS@UMG, Department of Health Science, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Antonio Leo
- Section of Pharmacology, Science of Health Department, School of Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (L.G.); (F.B.); (S.C.); (M.T.); (L.G.); (V.R.); (A.L.); (G.D.S.)
- Research Center FAS@UMG, Department of Health Science, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Giovambattista De Sarro
- Section of Pharmacology, Science of Health Department, School of Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (L.G.); (F.B.); (S.C.); (M.T.); (L.G.); (V.R.); (A.L.); (G.D.S.)
- Research Center FAS@UMG, Department of Health Science, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
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11
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Jeong HR, Hwang IT. MicroRNAs as novel biomarkers for the diagnosis and treatment of pediatric diseases. Clin Exp Pediatr 2024; 67:119-125. [PMID: 37232075 PMCID: PMC10915459 DOI: 10.3345/cep.2023.00171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 04/22/2023] [Accepted: 04/24/2023] [Indexed: 05/27/2023] Open
Abstract
MicroRNAs (miRNAs) are highly conserved noncoding RNAs that regulate gene expression by silencing or degrading messenger RNAs. Many of the approximately 2,500 miRNAs discovered in humans are known to regulate vital biological processes, including cell differentiation, proliferation, apoptosis, and embryonic tissue development. Aberrant miRNA expression may have pathological and malignant consequences. Therefore, miRNAs have emerged as novel diagnostic markers and potential therapeutic targets for various diseases. Children undergo various stages of growth, development, and maturation between birth and adulthood. It is important to study the role of miRNA expression in normal growth and disease development during these developmental stages. In this mini-review, we discuss the role of miRNAs as diagnostic and prognostic biomarkers in various pediatric diseases.
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Affiliation(s)
- Hwal Rim Jeong
- Department of Pediatrics, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Il Tae Hwang
- Department of Pediatrics, Hallym University Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
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12
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Abdel Mageed SS, Rashad AA, Elshaer SS, Elballal MS, Mohammed OA, Darwish SF, Salama RM, Mangoura SA, Al-Noshokaty TM, Gomaa RM, Elesawy AE, El-Demerdash AA, Zaki MB, Abulsoud AI, El-Dakroury WA, Elrebehy MA, Abdel-Reheim MA, Moustafa YM, Gedawy EM, Doghish AS. The emerging role of miRNAs in epilepsy: From molecular signatures to diagnostic potential. Pathol Res Pract 2024; 254:155146. [PMID: 38266457 DOI: 10.1016/j.prp.2024.155146] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/15/2024] [Accepted: 01/17/2024] [Indexed: 01/26/2024]
Abstract
Epilepsy is a medical condition characterized by intermittent seizures accompanied by changes in consciousness. Epilepsy significantly impairs the daily functioning and overall well-being of affected individuals. Epilepsy is a chronic neurological disorder characterized by recurrent seizures resulting from various dysfunctions in brain activity. The molecular processes underlying changes in neuronal structure, impaired apoptotic responses in neurons, and disruption of regenerative pathways in glial cells in epilepsy remain unknown. MicroRNAs (miRNAs) play a crucial role in regulating apoptosis, autophagy, oxidative stress, neuroinflammation, and the body's regenerative and immune responses. miRNAs have been shown to influence many pathogenic processes in epilepsy including inflammatory responses, neuronal necrosis and apoptosis, dendritic growth, synaptic remodeling, and other processes related to the development of epilepsy. Therefore, the purpose of our current analysis was to determine the role of miRNAs in the etiology and progression of epilepsy. Furthermore, they have been examined for their potential application as biomarkers and therapeutic targets.
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Affiliation(s)
- Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed A Rashad
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Shereen Saeid Elshaer
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Department of Biochemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo 11823, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Samar F Darwish
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Rania M Salama
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Misr International University (MIU), Cairo, Egypt
| | - Safwat Abdelhady Mangoura
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Tohada M Al-Noshokaty
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Rania M Gomaa
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Pharmaceutical Industries, Badr University in Cairo (BUC), Badr City, P.O. Box 11829, Cairo, Egypt
| | - Ahmed E Elesawy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Aya A El-Demerdash
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt
| | - Ahmed I Abulsoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231 Cairo, Egypt.
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62521, Egypt.
| | - Yasser M Moustafa
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ehab M Gedawy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Pharmaceutical Industries, Badr University in Cairo (BUC), Badr City, P.O. Box 11829, Cairo, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231 Cairo, Egypt.
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13
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Sharma AA, Szaflarski JP. The longitudinal effects of cannabidiol on brain temperature in patients with treatment-resistant epilepsy. Epilepsy Behav 2024; 151:109606. [PMID: 38199054 DOI: 10.1016/j.yebeh.2023.109606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 12/21/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024]
Abstract
Neuroinflammation (NI) is a key pathophysiological contributor to treatment-resistant epilepsy (TRE) that remains challenging to observe in vivo. Magnetic resonance spectroscopic imaging and thermometry (MRSI-t) is an emerging technique that can be used to non-invasively map brain temperature, whereby brain temperature elevations serve as a surrogate for the cellular and biochemical processes associated with NI. In a previous multimodal imaging study of focal epilepsy patients, we observed MRSI-t-based brain temperature elevations ipsilateral to the seizure onset zone (SOZ) that were concordant with evidence of edema (Sharma et al., 2023). Despite its potential as tool, it is unclear if MRSI-t can monitor changes in brain temperature in response to treatment. We imaged 25 participants approximately 12-weeks apart. Eight patients with TRE were imaged before receiving highly-purified pharmaceutical grade cannabidiol (CBD; pre-CBD) and after 12-weeks of CBD (on-CBD) therapy. Seventeen healthy controls (HCs) were also imaged twice. Repeated measures t-tests computed changes in TRE patients' seizure symptoms, mood, and brain temperature within their respective SOZs. Repeated measures ANOVAs tested Group*Time changes in imaging data. Participants with TRE had abnormally high peak brain temperatures within their SOZs that decreased after CBD initiation (p < 0.0001). Seizure severity scores also improved after CBD initiation (p < 0.001). These findings provide insights into the possible neural effects of CBD, and further demonstrate MRSI-t's potential as a tool for delineating SOZ. Further investigations into MRSI-t as a longitudinal measure of therapy-induced changes in NI are warranted.
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Affiliation(s)
- Ayushe A Sharma
- Department of Neurology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA; Department of Neurobiology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
| | - Jerzy P Szaflarski
- Department of Neurology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA; Department of Neurobiology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA; Department of Neurosurgery, University of Alabama at Birmingham (UAB), Birmingham, AL, USA; University of Alabama at Birmingham Epilepsy Center (UABEC), Birmingham, AL, USA.
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14
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Hlauschek G, Nicolo J, Sinclair B, Law M, Yasuda CL, Cendes F, Lossius MI, Kwan P, Vivash L. Role of the glymphatic system and perivascular spaces as a potential biomarker for post-stroke epilepsy. Epilepsia Open 2024; 9:60-76. [PMID: 38041607 PMCID: PMC10839409 DOI: 10.1002/epi4.12877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 11/29/2023] [Indexed: 12/03/2023] Open
Abstract
Stroke is one of the most common causes of acquired epilepsy, which can also result in disability and increased mortality rates particularly in elderly patients. No preventive treatment for post-stroke epilepsy is currently available. Development of such treatments has been greatly limited by the lack of biomarkers to reliably identify high-risk patients. The glymphatic system, including perivascular spaces (PVS), is the brain's waste clearance system, and enlargement or asymmetry of PVS (ePVS) is hypothesized to play a significant role in the pathogenesis of several neurological conditions. In this article, we discuss potential mechanisms for the role of perivascular spaces in the development of post-stroke epilepsy. Using advanced MR-imaging techniques, it has been shown that there is asymmetry and impairment of glymphatic function in the setting of ischemic stroke. Furthermore, studies have described a dysfunction of PVS in patients with different focal and generalized epilepsy syndromes. It is thought that inflammatory processes involving PVS and the blood-brain barrier, impairment of waste clearance, and sustained hypertension affecting the glymphatic system during a seizure may play a crucial role in epileptogenesis post-stroke. We hypothesize that impairment of the glymphatic system and asymmetry and dynamics of ePVS in the course of a stroke contribute to the development of PSE. Automated ePVS detection in stroke patients might thus assist in the identification of high-risk patients for post-stroke epilepsy trials. PLAIN LANGUAGE SUMMARY: Stroke often leads to epilepsy and is one of the main causes of epilepsy in elderly patients, with no preventative treatment available. The brain's waste removal system, called the glymphatic system which consists of perivascular spaces, may be involved. Enlargement or asymmetry of perivascular spaces could play a role in this and can be visualised with advanced brain imaging after a stroke. Detecting enlarged perivascular spaces in stroke patients could help identify those at risk for post-stroke epilepsy.
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Affiliation(s)
- Gernot Hlauschek
- Division of Clinical Neuroscience, National Centre for Epilepsy, member of ERN EpicareOslo University HospitalNorway
- The University of OsloOsloNorway
- Department of Neurosciences, Central Clinical SchoolMonash UniversityMelbourneVictoriaAustralia
| | - John‐Paul Nicolo
- Department of Neurosciences, Central Clinical SchoolMonash UniversityMelbourneVictoriaAustralia
- Department of NeurologyThe AlfredMelbourneVictoriaAustralia
- Departments of Medicine and NeurologyThe University of Melbourne, Royal Melbourne HospitalParkvilleVictoriaAustralia
| | - Benjamin Sinclair
- Department of Neurosciences, Central Clinical SchoolMonash UniversityMelbourneVictoriaAustralia
- Department of NeurologyThe AlfredMelbourneVictoriaAustralia
| | - Meng Law
- Department of Neurosciences, Central Clinical SchoolMonash UniversityMelbourneVictoriaAustralia
- Department of RadiologyThe AlfredMelbourneVictoriaAustralia
| | | | | | - Morten Ingvar Lossius
- Division of Clinical Neuroscience, National Centre for Epilepsy, member of ERN EpicareOslo University HospitalNorway
- The University of OsloOsloNorway
| | - Patrick Kwan
- Department of Neurosciences, Central Clinical SchoolMonash UniversityMelbourneVictoriaAustralia
- Department of NeurologyThe AlfredMelbourneVictoriaAustralia
- Departments of Medicine and NeurologyThe University of Melbourne, Royal Melbourne HospitalParkvilleVictoriaAustralia
| | - Lucy Vivash
- Department of Neurosciences, Central Clinical SchoolMonash UniversityMelbourneVictoriaAustralia
- Department of NeurologyThe AlfredMelbourneVictoriaAustralia
- Departments of Medicine and NeurologyThe University of Melbourne, Royal Melbourne HospitalParkvilleVictoriaAustralia
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15
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Chen S, Huang M, Xu D, Li M. Epigenetic regulation in epilepsy: A novel mechanism and therapeutic strategy for epilepsy. Neurochem Int 2024; 173:105657. [PMID: 38145842 DOI: 10.1016/j.neuint.2023.105657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 12/02/2023] [Accepted: 12/14/2023] [Indexed: 12/27/2023]
Abstract
Epilepsy is a common neurological disorder characterized by recurrent seizures with excessive and abnormal neuronal discharges. Epileptogenesis is usually involved in neuropathological processes such as ion channel dysfunction, neuronal injury, inflammatory response, synaptic plasticity, gliocyte proliferation and mossy fiber sprouting, currently the pathogenesis of epilepsy is not yet completely understood. A growing body of studies have shown that epigenetic regulation, such as histone modifications, DNA methylation, noncoding RNAs (ncRNAs), N6-methyladenosine (m6A) and restrictive element-1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) are also involved in epilepsy. Through epigenetic studies, we found that the synaptic dysfunction, nerve damage, cognitive dysfunction and brain development abnormalities are affected by epigenetic regulation of epilepsy-related genes in patients with epilepsy. However, the functional roles of epigenetics in pathogenesis and treatment of epilepsy are still to be explored. Therefore, profiling the array of genes that are epigenetically dysregulated in epileptogenesis is likely to advance our understanding of the mechanisms underlying the pathophysiology of epilepsy and may for the amelioration of these serious human conditions provide novel insight into therapeutic strategies and diagnostic biomarkers for epilepsy to improve serious human condition.
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Affiliation(s)
- Shuang Chen
- Department of Neurology, Hubei Provincial Hospital of Integrated Chinese and Western Medicine, Hubei University of Chinese Medicine, Wuhan, 430000, China
| | - Ming Huang
- Department of Neurology, Hubei Provincial Hospital of Integrated Chinese and Western Medicine, Hubei University of Chinese Medicine, Wuhan, 430000, China
| | - Da Xu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Man Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
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16
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McGann AM, Westerkamp GC, Chalasani A, Danzer CSK, Parkins EV, Rajathi V, Horn PS, Pedapati EV, Tiwari D, Danzer SC, Gross C. MiR-324-5p inhibition after intrahippocampal kainic acid-induced status epilepticus does not prevent epileptogenesis in mice. Front Neurol 2023; 14:1280606. [PMID: 38033777 PMCID: PMC10687438 DOI: 10.3389/fneur.2023.1280606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 10/20/2023] [Indexed: 12/02/2023] Open
Abstract
Background Acquired epilepsies are caused by an initial brain insult that is followed by epileptogenesis and finally the development of spontaneous recurrent seizures. The mechanisms underlying epileptogenesis are not fully understood. MicroRNAs regulate mRNA translation and stability and are frequently implicated in epilepsy. For example, antagonism of a specific microRNA, miR-324-5p, before brain insult and in a model of chronic epilepsy decreases seizure susceptibility and frequency, respectively. Here, we tested whether antagonism of miR-324-5p during epileptogenesis inhibits the development of epilepsy. Methods We used the intrahippocampal kainic acid (IHpKa) model to initiate epileptogenesis in male wild type C57BL/6 J mice aged 6-8 weeks. Twenty-four hours after IHpKa, we administered a miR-324-5p or scrambled control antagomir intracerebroventricularly and implanted cortical surface electrodes for EEG monitoring. EEG data was collected for 28 days and analyzed for seizure frequency and duration, interictal spike activity, and EEG power. Brains were collected for histological analysis. Results Histological analysis of brain tissue showed that IHpKa caused characteristic hippocampal damage in most mice regardless of treatment. Antagomir treatment did not affect latency to, frequency, or duration of spontaneous recurrent seizures or interictal spike activity but did alter the temporal development of frequency band-specific EEG power. Conclusion These results suggest that miR-324-5p inhibition during epileptogenesis induced by status epilepticus does not convey anti-epileptogenic effects despite having subtle effects on EEG frequency bands. Our results highlight the importance of timing of intervention across epilepsy development and suggest that miR-324-5p may act primarily as a proconvulsant rather than a pro-epileptogenic regulator.
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Affiliation(s)
- Amanda M. McGann
- Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Neuroscience Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Grace C. Westerkamp
- Division of Child and Adolescent Psychiatry, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Alisha Chalasani
- Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Cole S. K. Danzer
- Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Emma V. Parkins
- Neuroscience Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Valerine Rajathi
- Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Paul S. Horn
- Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Ernest V. Pedapati
- Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Division of Child and Adolescent Psychiatry, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Durgesh Tiwari
- Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Steve C. Danzer
- Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Neuroscience Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Anesthesia, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Department of Anesthesia, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Christina Gross
- Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Neuroscience Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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17
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Fan L, Liu L, Rao X, Wang X, Luo H, Gan J. The 100 most-cited manuscripts in epilepsy epigenetics: a bibliometric analysis. Childs Nerv Syst 2023; 39:3111-3122. [PMID: 37340273 PMCID: PMC10643235 DOI: 10.1007/s00381-023-06032-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 06/12/2023] [Indexed: 06/22/2023]
Abstract
PURPOSE The top citation article reflects the developmental milestone of a given field. The purpose of this bibliometric analysis was to identify and assess the 100 most-cited (T100) articles on the epigenetics mechanism of epilepsy. METHODS The Web of Science Core Collection (WoSCC) database was used to investigate, and search terms related to epilepsy epigenetics were compiled. Results were ranked according to citation number. The publication year, citation density, authorship, journal, country, institution, manuscript type, theme, and clinical topics were further evaluated. RESULTS The Web of Science search returned a total of 1231 manuscripts. The number of citations for a manuscript ranges from 739 to 75. The greatest number of manuscripts in the top 100 was published in the Human Molecular Genetics and Neurobiology of Disease (n = 4). The journal with the highest 2021 impact factor was Nature Medicine (IF = 87.244). The most-cited paper by Aid et al. reported a new nomenclature for mouse and rat BDNF gene and its expression profiles. Most manuscripts were original articles (n = 69), of which 52 (75.4%) report findings of basic scientific work. The most prevalent theme was microRNA (n = 29), and the most popular clinical topic was temporal lobe epilepsy (n = 13). CONCLUSIONS The research on the epigenetics mechanism of epilepsy was in its infancy but full of potential. The developmental history and current achievements of hot themes, including microRNA, DNA methylation, and temporal lobe epilepsy, were overviewed. This bibliometric analysis provides useful information and insight for researchers when launching new projects.
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Affiliation(s)
- Lijuan Fan
- Department of Pediatrics, West China Second University Hospital, Sichuan University, No. 20, Section 3, South Renmin Road, Chengdu, 610041, Sichuan Province, China
- Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Development and Maternal and Child Diseases of Sichuan Province, Chengdu, Sichuan, China
| | - Lu Liu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, No. 20, Section 3, South Renmin Road, Chengdu, 610041, Sichuan Province, China
- West China School of Public Health, Sichuan University, Chengdu, Sichuan Province, China
| | - Xueyi Rao
- Department of Pediatrics, West China Second University Hospital, Sichuan University, No. 20, Section 3, South Renmin Road, Chengdu, 610041, Sichuan Province, China
- Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Development and Maternal and Child Diseases of Sichuan Province, Chengdu, Sichuan, China
| | - Xiaoqian Wang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, No. 20, Section 3, South Renmin Road, Chengdu, 610041, Sichuan Province, China
- Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Development and Maternal and Child Diseases of Sichuan Province, Chengdu, Sichuan, China
| | - Huan Luo
- Department of Pediatrics, West China Second University Hospital, Sichuan University, No. 20, Section 3, South Renmin Road, Chengdu, 610041, Sichuan Province, China
- Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Development and Maternal and Child Diseases of Sichuan Province, Chengdu, Sichuan, China
| | - Jing Gan
- Department of Pediatrics, West China Second University Hospital, Sichuan University, No. 20, Section 3, South Renmin Road, Chengdu, 610041, Sichuan Province, China.
- Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, Sichuan, China.
- Key Laboratory of Development and Maternal and Child Diseases of Sichuan Province, Chengdu, Sichuan, China.
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18
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Brindley E, Heiland M, Mooney C, Diviney M, Mamad O, Hill TDM, Yan Y, Venø MT, Reschke CR, Batool A, Langa E, Sanz-Rodriguez A, Heller JP, Morris G, Conboy K, Kjems J, Brennan GP, Henshall DC. Brain cell-specific origin of circulating microRNA biomarkers in experimental temporal lobe epilepsy. Front Mol Neurosci 2023; 16:1230942. [PMID: 37808470 PMCID: PMC10556253 DOI: 10.3389/fnmol.2023.1230942] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 09/07/2023] [Indexed: 10/10/2023] Open
Abstract
The diagnosis of epilepsy is complex and challenging and would benefit from the availability of molecular biomarkers, ideally measurable in a biofluid such as blood. Experimental and human epilepsy are associated with altered brain and blood levels of various microRNAs (miRNAs). Evidence is lacking, however, as to whether any of the circulating pool of miRNAs originates from the brain. To explore the link between circulating miRNAs and the pathophysiology of epilepsy, we first sequenced argonaute 2 (Ago2)-bound miRNAs in plasma samples collected from mice subject to status epilepticus induced by intraamygdala microinjection of kainic acid. This identified time-dependent changes in plasma levels of miRNAs with known neuronal and microglial-cell origins. To explore whether the circulating miRNAs had originated from the brain, we generated mice expressing FLAG-Ago2 in neurons or microglia using tamoxifen-inducible Thy1 or Cx3cr1 promoters, respectively. FLAG immunoprecipitates from the plasma of these mice after seizures contained miRNAs, including let-7i-5p and miR-19b-3p. Taken together, these studies confirm that a portion of the circulating pool of miRNAs in experimental epilepsy originates from the brain, increasing support for miRNAs as mechanistic biomarkers of epilepsy.
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Affiliation(s)
- Elizabeth Brindley
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Mona Heiland
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Catherine Mooney
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- School of Computer Science, University College Dublin, Dublin, Ireland
| | - Mairead Diviney
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Omar Mamad
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Thomas D. M. Hill
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Yan Yan
- Interdisciplinary Nanoscience Centre (iNANO) and Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
- Omiics ApS, Aarhus, Denmark
| | - Morten T. Venø
- Interdisciplinary Nanoscience Centre (iNANO) and Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
- Omiics ApS, Aarhus, Denmark
| | - Cristina R. Reschke
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Aasia Batool
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Elena Langa
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Amaya Sanz-Rodriguez
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Janosch P. Heller
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- School of Biotechnology, Dublin City University, Dublin, Ireland
| | - Gareth Morris
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
- Division of Neuroscience, Faculty of Biology, Medicine and Health, School of Biological Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| | - Karen Conboy
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Jørgen Kjems
- Interdisciplinary Nanoscience Centre (iNANO) and Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Gary P. Brennan
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- School of Biomolecular and Biomedical Sciences, Conway Institute, University College Dublin, Dublin, Ireland
| | - David C. Henshall
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
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19
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Xie G, Chen H, He C, Hu S, Xiao X, Luo Q. The dysregulation of miRNAs in epilepsy and their regulatory role in inflammation and apoptosis. Funct Integr Genomics 2023; 23:287. [PMID: 37653173 PMCID: PMC10471759 DOI: 10.1007/s10142-023-01220-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 08/22/2023] [Accepted: 08/26/2023] [Indexed: 09/02/2023]
Abstract
Epilepsy is a neurological disorder that impacts millions of people worldwide, and it is characterized by the occurrence of recurrent seizures. The pathogenesis of epilepsy is complex, involving dysregulation of various genes and signaling pathways. MicroRNAs (miRNAs) are a group of small non-coding RNAs that play a vital role in the regulation of gene expression. They have been found to be involved in the pathogenesis of epilepsy, acting as key regulators of neuronal excitability and synaptic plasticity. In recent years, there has been a growing interest in exploring the miRNA regulatory network in epilepsy. This review summarizes the current knowledge of the regulatory miRNAs involved in inflammation and apoptosis in epilepsy and discusses its potential as a new avenue for developing targeted therapies for the treatment of epilepsy.
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Affiliation(s)
- Guoping Xie
- Department of Clinical Laboratory, The Second Staff Hospital of Wuhan Iron and Steel (Group) Corporation, Wuhan, Hubei, China
| | - Huan Chen
- Department of Clinical Laboratory, Wuhan Institute of Technology Hospital, Wuhan Institute of Technology, Wuhan, China
| | - Chan He
- Department of Clinical Laboratory, Maternal and Child Health Hospital in Wuchang District, Wuhan, Hubei, China
| | - Siheng Hu
- Department of Clinical Laboratory, Honggangcheng Street Community Health Service Center, Qingshan District, Wuhan, Hubei, China
| | - Xue Xiao
- Department of Clinical Laboratory, Gongrencun Street Community Health Service Center, Wuhan, China
| | - Qunying Luo
- Department of Neurology, Huarun Wuhan Iron and Steel General Hospital, Wuhan, Hubei, China.
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20
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Lam P, Newland J, Faull RLM, Kwakowsky A. Cation-Chloride Cotransporters KCC2 and NKCC1 as Therapeutic Targets in Neurological and Neuropsychiatric Disorders. Molecules 2023; 28:1344. [PMID: 36771011 PMCID: PMC9920462 DOI: 10.3390/molecules28031344] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/21/2023] [Accepted: 01/25/2023] [Indexed: 02/04/2023] Open
Abstract
Neurological diseases including Alzheimer's, Huntington's disease, Parkinson's disease, Down syndrome and epilepsy, and neuropsychiatric disorders such as schizophrenia, are conditions that affect not only individuals but societies on a global scale. Current therapies offer a means for small symptomatic relief, but recently there has been increasing demand for therapeutic alternatives. The γ-aminobutyric acid (GABA)ergic signaling system has been investigated for developing new therapies as it has been noted that any dysfunction or changes to this system can contribute to disease progression. Expression of the K-Cl-2 (KCC2) and N-K-C1-1 (NKCC1) cation-chloride cotransporters (CCCs) has recently been linked to the disruption of GABAergic activity by affecting the polarity of GABAA receptor signaling. KCC2 and NKCC1 play a part in multiple neurological and neuropsychiatric disorders, making them a target of interest for potential therapies. This review explores current research suggesting the pathophysiological role and therapeutic importance of KCC2 and NKCC1 in neuropsychiatric and neurological disorders.
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Affiliation(s)
- Patricia Lam
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Julia Newland
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Richard L. M. Faull
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Andrea Kwakowsky
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
- Pharmacology and Therapeutics, School of Medicine, Galway Neuroscience Centre, University of Galway, H91 W5P7 Galway, Ireland
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21
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Mao S, Wu J, Yan J, Zhang W, Zhu F. Dysregulation of miR-146a: a causative factor in epilepsy pathogenesis, diagnosis, and prognosis. Front Neurol 2023; 14:1094709. [PMID: 37213914 PMCID: PMC10196196 DOI: 10.3389/fneur.2023.1094709] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 04/03/2023] [Indexed: 05/23/2023] Open
Abstract
miR-146a is an NF-κB-dependent miRNA that acts as an anti-inflammatory miRNA via the Toll-like receptor (TLR) pathway. miR-146a targets multiple genes and has been identified to directly or indirectly regulate processes other than inflammation, including intracellular Ca changes, apoptosis, oxidative stress, and neurodegeneration. miR-146a is an important regulator of gene expression in epilepsy development and progression. Furthermore, miR-146a-related single nucleotide polymorphisms (SNPs) and single nucleotide variants (SNVs) contribute to the genetic susceptibility to drug resistance and seizure severity in epilepsy patients. This study summarizes the abnormal expression patterns of miR-146a in different types and stages of epilepsy and its potential molecular regulation mechanism, indicating that miR-146a can be used as a novel biomarker for epilepsy diagnosis, prognosis, and treatment.
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Affiliation(s)
- Shiqi Mao
- Department of Clinical Medicine, School of Medicine, Zhejiang University City College, Hangzhou, China
| | - Jinhan Wu
- Department of Clinical Medicine, School of Medicine, Zhejiang University City College, Hangzhou, China
| | - Jingkai Yan
- Department of Clinical Medicine, School of Medicine, Zhejiang University City College, Hangzhou, China
| | - Weijun Zhang
- Department of Neurology, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, China
- *Correspondence: Weijun Zhang
| | - Feng Zhu
- Department of Clinical Medicine, School of Medicine, Zhejiang University City College, Hangzhou, China
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Zhejiang University City College, Hangzhou, China
- Feng Zhu
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22
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Stage- and Subfield-Associated Hippocampal miRNA Expression Patterns after Pilocarpine-Induced Status Epilepticus. Biomedicines 2022; 10:biomedicines10123012. [PMID: 36551767 PMCID: PMC9775180 DOI: 10.3390/biomedicines10123012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/15/2022] [Accepted: 11/16/2022] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVE To investigate microRNA (miRNA) expression profiles before and after pilocarpine-induced status epilepticus (SE) in the cornu ammonis (CA) and dentated gyrus (DG) areas of the mouse hippocampus, and to predict the downstream proteins and related pathways based on bioinformatic analysis. METHODS An epileptic mouse model was established using a pilocarpine injection. Brain tissues from the CA and DG were collected separately for miRNA analysis. The miRNAs were extracted using a kit, and the expression profiles were generated using the SurePrint G3 Mouse miRNA microarray and validated. The intersecting genes of TargetScan and miRanda were selected to predict the target genes of each miRNA. For gene ontology (GO) studies, the parent-child-intersection (pci) method was used for enrichment analysis, and Benjamini-Hochberg was used for multiple test correction. The Kyoto Encyclopedia of Genes and Genomes (KEGG) was used to detect disease-related pathways among the large list of miRNA-targeted genes. All analyses mentioned above were performed at the time points of control, days 3, 14, and 60 post-SE. RESULTS Control versus days 3, 14, and 60 post-SE: in the CA area, a total of 131 miRNAs were differentially expressed; 53, 49, and 26 miRNAs were upregulated and 54, 10, and 22 were downregulated, respectively. In the DG area, a total of 171 miRNAs were differentially expressed; furthermore, 36, 32, and 28 miRNAs were upregulated and 78, 58, and 44 were downregulated, respectively. Of these, 92 changed in both the CA and DG, 39 only in the CA, and 79 only in the DG area. The differentially expressed miRNAs target 11-1630 genes. Most of these proteins have multiple functions in epileptogenesis. There were 15 common pathways related to altered miRNAs: nine different pathways in the CA and seven in the DG area. CONCLUSIONS Stage- and subfield-associated hippocampal miRNA expression patterns are closely related to epileptogenesis, although the detailed mechanisms need to be explored in the future.
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23
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Zhou HY, Huai YP, Jin X, Yan P, Tang XJ, Wang JY, Shi N, Niu M, Meng ZX, Wang X. An enriched environment reduces hippocampal inflammatory response and improves cognitive function in a mouse model of stroke. Neural Regen Res 2022; 17:2497-2503. [PMID: 35535902 PMCID: PMC9120675 DOI: 10.4103/1673-5374.338999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
An enriched environment is used as a behavioral intervention therapy that applies sensory, motor, and social stimulation, and has been used in basic and clinical research of various neurological diseases. In this study, we established mouse models of photothrombotic stroke and, 24 hours later, raised them in a standard, enriched, or isolated environment for 4 weeks. Compared with the mice raised in a standard environment, the cognitive function of mice raised in an enriched environment was better and the pathological damage in the hippocampal CA1 region was remarkably alleviated. Furthermore, protein expression levels of tumor necrosis factor receptor-associated factor 6, nuclear factor κB p65, interleukin-6, and tumor necrosis factor α, and the mRNA expression level of tumor necrosis factor receptor-associated factor 6 were greatly lower, while the expression level of miR-146a-5p was higher. Compared with the mice raised in a standard environment, changes in these indices in mice raised in an isolated environment were opposite to mice raised in an enriched environment. These findings suggest that different living environments affect the hippocampal inflammatory response and cognitive function in a mouse model of stroke. An enriched environment can improve cognitive function following stroke through up-regulation of miR-146a-5p expression and a reduction in the inflammatory response.
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Affiliation(s)
- Hong-Yu Zhou
- Department of Rehabilitation Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University (Clinical Medical College, Yangzhou University), Yangzhou, Jiangsu Province, China
| | - Ya-Ping Huai
- Department of Rehabilitation Medicine, Shenzhen Longhua District Central Hospital, Shenzhen, Guangdong Province, China
| | - Xing Jin
- Department of Rehabilitation Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University (Clinical Medical College, Yangzhou University), Yangzhou, Jiangsu Province, China
| | - Ping Yan
- School of Nursing, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Xiao-Jia Tang
- Department of Rehabilitation Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University (Clinical Medical College, Yangzhou University), Yangzhou, Jiangsu Province, China
| | - Jun-Ya Wang
- Department of Rehabilitation Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University (Clinical Medical College, Yangzhou University), Yangzhou, Jiangsu Province, China
| | - Nan Shi
- School of Nursing, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Meng Niu
- Dalian Medical University, Dalian, Liaoning Province, China
| | - Zhao-Xiang Meng
- Department of Rehabilitation Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University (Clinical Medical College, Yangzhou University), Yangzhou, Jiangsu Province, China
| | - Xin Wang
- Department of Rehabilitation Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University (Clinical Medical College, Yangzhou University), Yangzhou, Jiangsu Province, China
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24
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Chithanathan K, Jürgenson M, Guha M, Yan L, Žarkovskaja T, Pook M, Magilnick N, Boldin MP, Rebane A, Tian L, Zharkovsky A. Paradoxical attenuation of neuroinflammatory response upon LPS challenge in miR-146b deficient mice. Front Immunol 2022; 13:996415. [PMID: 36389659 PMCID: PMC9659615 DOI: 10.3389/fimmu.2022.996415] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 10/14/2022] [Indexed: 10/26/2023] Open
Abstract
The miR-146 family consists of two microRNAs (miRNAs), miR-146a and miR-146b (miR-146a/b), both of which are known to suppress immune responses in a variety of conditions. Here, we studied how constitutive deficiency of miR-146b (Mir146b-/-) affects lipopolysaccharide (LPS)-induced neuroinflammation in mice. Our experiments demonstrated that miR-146b deficiency results in the attenuation of LPS-induced neuroinflammation, as it was evidenced by the reduction of sickness behavior, a decrease in the inflammatory status of microglia, and the loss of morphological signs of microglial activation in the hippocampus. Gene expression analysis revealed that LPS-induced upregulation of hippocampal pro-inflammatory cytokines is attenuated in Mir146b-/- mice, compared to wild-type (WT) mice. In addition, reduced expression of the NF-κB nuclear protein p65, reduced miR-146 family target TLR4 expression and relatively stronger upregulation of miR-146a was found in Mir146b-/- mice as compared to WT mice upon LPS challenge. Compensatory upregulation of miR-146a can explain the attenuation of the LPS-induced neuroinflammation. This was supported by experiments conducted with miR-146a/b deficient mice (Mir146a/b-/-), which demonstrated that additional deletion of the miR-146a led to the restoration of LPS-induced sickness behavior and proinflammatory cytokines. Our experiments also showed that the observed upregulation of miR-146a in Mir146b-/- mice is due to the overexpression of a miR-146a transcription inducer, interferon regulatory factor 7 (Irf7). Altogether, our results show the existence of crosstalk between miR-146a and mir-146b in the regulation of LPS-induced neuroinflammation.
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Affiliation(s)
- Keerthana Chithanathan
- Department of Physiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia
| | - Monika Jürgenson
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Mithu Guha
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Ling Yan
- Department of Physiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia
| | - Tamara Žarkovskaja
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Martin Pook
- Department of Biomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Nathaniel Magilnick
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope National Medical Center, Duarte, CA, United States
| | - Mark P. Boldin
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope National Medical Center, Duarte, CA, United States
| | - Ana Rebane
- Department of Biomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Li Tian
- Department of Physiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia
| | - Alexander Zharkovsky
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
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25
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Zeng C, Hu J, Chen F, Huang T, Zhang L. The Coordination of mTOR Signaling and Non-Coding RNA in Regulating Epileptic Neuroinflammation. Front Immunol 2022; 13:924642. [PMID: 35898503 PMCID: PMC9310657 DOI: 10.3389/fimmu.2022.924642] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/16/2022] [Indexed: 11/13/2022] Open
Abstract
Epilepsy accounts for a significant proportion of the burden of neurological disorders. Neuroinflammation acting as the inflammatory response to epileptic seizures is characterized by aberrant regulation of inflammatory cells and molecules, and has been regarded as a key process in epilepsy where mTOR signaling serves as a pivotal modulator. Meanwhile, accumulating evidence has revealed that non-coding RNAs (ncRNAs) interfering with mTOR signaling are involved in neuroinflammation and therefore articipate in the development and progression of epilepsy. In this review, we highlight recent advances in the regulation of mTOR on neuroinflammatory cells and mediators, and feature the progresses of the interaction between ncRNAs and mTOR in epileptic neuroinflammation.
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Affiliation(s)
- Chudai Zeng
- Departments of Neurosurgery, and National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Jason Hu
- Department of Neonatology, Yale School of Medicine, New Haven, CT, United States
| | - Fenghua Chen
- Departments of Neurosurgery, and National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Fenghua Chen, ; Tianxiang Huang, ; Longbo Zhang,
| | - Tianxiang Huang
- Departments of Neurosurgery, and National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Fenghua Chen, ; Tianxiang Huang, ; Longbo Zhang,
| | - Longbo Zhang
- Departments of Neurosurgery, and National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT, United States
- *Correspondence: Fenghua Chen, ; Tianxiang Huang, ; Longbo Zhang,
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Yu T, Huo L, Lei J, Sun JJ, Wang H. Modulation of Microglia M2 Polarization and Alleviation of Hippocampal Neuron Injury By MiR-106b-5p/RGMa in a Mouse Model of Status Epilepticus. Inflammation 2022; 45:2223-2242. [PMID: 35789312 DOI: 10.1007/s10753-022-01686-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 05/19/2022] [Accepted: 05/19/2022] [Indexed: 11/30/2022]
Abstract
MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level. The miRNA miR-106b-5p has been linked to epilepsy, but its specific role and mechanism of action remain unclear. This was investigated in the present study using a mouse model of pilocarpine-induced status epilepticus and an in vitro system of HT22 hippocampal cells treated with Mg2+-free solution and cocultured with BV2 microglia cells. We found that inhibiting miR-106b-5p expression promoted microglia M2 polarization, reduced the inflammatory response, and alleviated neuronal injury. These effects involved modulation of the repulsive guidance molecule A (RGMa)-Rac1-c-Jun N-terminal kinase (JNK)/p38-mitogen-activated protein kinase (MAPK) signaling axis. Our results suggest that therapeutic strategies targeting miR-106b-5p or downstream factors can be effective in preventing epileptogenesis or treating epilepsy.
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Affiliation(s)
- Tao Yu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Liaoning Province, Shenyang City, 110004, China
| | - Liang Huo
- Department of Pediatrics, Shengjing Hospital of China Medical University, Liaoning Province, Shenyang City, 110004, China
| | - Jie Lei
- Department of Pediatrics, Shengjing Hospital of China Medical University, Liaoning Province, Shenyang City, 110004, China
| | - Jing-Jing Sun
- Department of Pediatrics, Shengjing Hospital of China Medical University, Liaoning Province, Shenyang City, 110004, China
| | - Hua Wang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Liaoning Province, Shenyang City, 110004, China.
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Dohm-Hansen S, Donoso F, Lucassen PJ, Clarke G, Nolan YM. The gut microbiome and adult hippocampal neurogenesis: A new focal point for epilepsy? Neurobiol Dis 2022; 170:105746. [DOI: 10.1016/j.nbd.2022.105746] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 04/13/2022] [Accepted: 04/29/2022] [Indexed: 02/07/2023] Open
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Mahjoob G, Ahmadi Y, Fatima rajani H, khanbabaei N, Abolhasani S. Circulating microRNAs as predictive biomarkers of coronary artery diseases in type 2 diabetes patients. J Clin Lab Anal 2022; 36:e24380. [PMID: 35349731 PMCID: PMC9102494 DOI: 10.1002/jcla.24380] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 03/16/2022] [Accepted: 03/17/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is an increasing metabolic disorder mostly resulting from unhealthy lifestyles. T2DM patients are prone to develop heart conditions such as coronary artery disease (CAD) which is a major cause of death in the world. Most clinical symptoms emerge at the advanced stages of CAD; therefore, establishing new biomarkers detectable in the early stages of the disease is crucial to enhance the efficiency of treatment. Recently, a significant body of evidence has shown alteration in miRNA levels associate with dysregulated gene expression occurring in T2DM and CAD, highlighting significance of circulating miRNAs in early detection of CAD arising from T2DM. Therefore, it seems crucial to establish a link between the miRNAs prognosing value and development of CAD in T2DM. AIM This study provides an overview on the alterations of the circulatory miRNAs in T2DM and various CADs and consider the potentials of miRNAs as biomarkers prognosing CADs in T2DM patients. MATERIALS AND METHODS Literature search was conducted for miRNAs involved in development of T2DM and CAD using the following key words: "miRNAs", "Biomarker", "Diabetes Mellitus Type 2 (T2DM)", "coronary artery diseases (CAD)". Articles written in the English language. RESULT There has been shown a rise in miR-375, miR-9, miR-30a-5p, miR-150, miR-9, miR-29a, miR-30d, miR-34a, miR-124a, miR-146a, miR-27a, and miR-320a in T2DM; whereas, miR-126, miR-21, miR-103, miR-28-3p, miR-15a, miR-145, miR-375, miR-223 have been shown to decrease. In addition to T2DM, some miRNAs such as mirR-1, miR-122, miR-132, and miR-133 play a part in development of subclinical aortic atherosclerosis associated with metabolic syndrome. Some miRNAs increase in both T2DM and CAD such as miR-1, miR-132, miR-133, and miR-373-3-p. More interestingly, some of these miRNAs such as miR-92a elevate years before emerging CAD in T2DM. CONCLUSION dysregulation of miRNAs plays outstanding roles in development of T2DM and CAD. Also, elevation of some miRNAs such as miR-92a in T2DM patients can efficiently prognose development of CAD in these patients, so these miRNAs can be used as biomarkers in this regard.
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Affiliation(s)
- Golnoosh Mahjoob
- Department of Clinical BiochemistrySarab Faculty of Medical Sciences.SarabIran
- Department of Clinical BiochemistryTarbiat Modares UniversityTehranIran
| | - Yasin Ahmadi
- Department of Medical Laboratory SciencesCollege of ScienceKomar University of Science and TechnologySulaimaniIraq
| | - Huda Fatima rajani
- Department of medical biotechnologySchool of advanced sciences in medicineTehran University of medical sciencesTehranIran
| | - Nafiseh khanbabaei
- Department of Clinical BiochemistrySarab Faculty of Medical Sciences.SarabIran
- Department of Clinical BiochemistryTarbiat Modares UniversityTehranIran
| | - Sakhavat Abolhasani
- Department of Clinical BiochemistrySarab Faculty of Medical Sciences.SarabIran
- Department of Clinical BiochemistryTarbiat Modares UniversityTehranIran
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Association of Polymorphisms in miR146a, an Inflammation-Associated MicroRNA, with the Risk of Idiopathic Recurrent Spontaneous Miscarriage: A Case-Control Study. DISEASE MARKERS 2022; 2022:1495082. [PMID: 35535334 PMCID: PMC9078850 DOI: 10.1155/2022/1495082] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 04/09/2022] [Accepted: 04/13/2022] [Indexed: 12/02/2022]
Abstract
It has been established that microRNAs (miRNAs) are involved in the regulation of immune responses and serve as biomarkers of inflammatory diseases as well as recurrent spontaneous miscarriage (RSM). Herein, we aimed to study the relationship between three functional miR146a gene polymorphisms with idiopathic RSM (IRSM) susceptibility. We recruited 161 patients with IRSM and 177 healthy women with at least one live birth and without a history of abortion. Genotyping was performed using RFLP-PCR and ARMS-PCR methods. We found that the rs6864584 T/C decreased the risk of IRSM under dominant TT+TC vs. CC (OR = 0.029) and allelic C vs. T (OR = 0.028) contrast models. Regarding rs2961920 A/C and rs57095329 A/G polymorphisms, the enhanced risk of IRSM was observed under different genetic contrasted models, including the codominant CC vs. AA (OR = 2.81 for rs2961920) and codominant GG vs. AA (OR = 2.36 for rs57095329). After applying a Bonferroni correction, haplotype analysis revealed a 51% decreased risk of IRSM regarding the ACA genotype combination. This is the first study reporting that miR146a rs57095329 A/G, rs2961920A/C, and rs6864584 T/C polymorphisms are associated with the risk of IRSM in a southern Iranian population. Performing replicated case-control studies on other ethnicities is warranted to outline the precise effects of the studied variants on the risk of gestational trophoblastic disorders.
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Ünalp A, Coskunpinar E, Gunduz K, Pekuz S, Baysal BT, Edizer S, Hayretdag C, Gudeloglu E. Detection of Deregulated miRNAs in Childhood Epileptic Encephalopathies. J Mol Neurosci 2022; 72:1234-1242. [PMID: 35461401 DOI: 10.1007/s12031-022-02001-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 03/15/2022] [Indexed: 01/07/2023]
Abstract
The term "epileptic encephalopathy" is used to describe a possible relationship between epilepsy and developmental delay. The pathogenesis of developmental encephalopathies, independent of epilepsy, can be defined by genetic control mechanisms. The aim of this study was to investigate the use of miRNAs as serum biomarkers for the determination and discrimination of epileptic encephalopathies. Whole blood samples obtained from 54 individuals in 2 groups designated as epileptic encephalopathy patients' group (n = 24) and healthy controls (n = 30) were included in this study. The expression levels of 10 miRNAs were determined using qRT-PCR. After the determination of expression levels, the correlation of upregulated miRNA levels and Ki67 index was calculated using Pearson correlation test. The comparison of epileptic encephalopathy patients' group with healthy controls revealed the upregulation of one miRNAs (hsa-miR-324-5p) and downregulation of three miRNAs (hsa-miR-146a-5p, hsa-miR-138-5p, hsa-miR-187-3p). It has been determined that miRNAs with altered expression are an important factor in the formation of epileptic seizures and seizure-induced neuronal death. The fact that processes that play a key role in epiloptogenesis are under the control of miRNAs causes miRNAs to become meta-controllers of gene expression in the brain. We thought that further studies are needed to prove that especially hsa-miR-146a-5p, hsa-miR-138-5p, and hsa-miR-187-3p can be used as epileptic encephalopathy biomarkers. The detection of disease-specific miRNAs could contribute to the development of precision treatments.
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Affiliation(s)
- Aycan Ünalp
- Department of Pediatric Neurology, Izmir Faculty of Medicine, University of Health Sciences, Izmir, Turkey.
| | - Ender Coskunpinar
- Department of Medical Biology, School of Medicine, University of Health Sciences, Istanbul, Turkey
| | - Kubra Gunduz
- Department of Medical Biology, School of Medicine, University of Health Sciences, Istanbul, Turkey
| | - Serdar Pekuz
- Department of Pediatric Neurology, University of Health Sciences, Dr. Behcet Uz Children's Training and Research Hospital, Izmir, Turkey
| | - Bahar Toklu Baysal
- Department of Pediatric Neurology, University of Health Sciences, Dr. Behcet Uz Children's Training and Research Hospital, Izmir, Turkey
| | - Selvinaz Edizer
- Department of Pediatric Neurology, University of Health Sciences, Dr. Behcet Uz Children's Training and Research Hospital, Izmir, Turkey
| | - Ceyda Hayretdag
- Department of Neurology, School of Medicine, Beykent University, Istanbul, Turkey
| | - Elif Gudeloglu
- Department of Pediatric Neurology, University of Health Sciences, Dr. Behcet Uz Children's Training and Research Hospital, Izmir, Turkey
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Pala M, Meral I, Pala Acikgoz N, Gorucu Yilmaz Ş, Taslidere E, Okur SK, Acar S, Akbas F. Pentylenetetrazole-induced kindling rat model: miR-182 and miR-27b-3p mediated neuroprotective effect of thymoquinone in the hippocampus. Neurol Res 2022; 44:726-737. [DOI: 10.1080/01616412.2022.2051129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Mukaddes Pala
- Faculty of Medicine, Department of Physiology, Malatya Turgut Ozal University, Malatya, Turkey
| | - Ismail Meral
- Faculty of Medicine, Department of Physiology, Bezmialem Vakif University, Istanbul, Turkey
| | - Nilgun Pala Acikgoz
- Faculty of Medicine, Department of Neurology, Bezmialem Vakif University, Istanbul, Turkey
| | - Şenay Gorucu Yilmaz
- Department of Nutrition and Dietetics, Gaziantep University, Gaziantep, Turkey
| | - Elif Taslidere
- Faculty of Medicine, Department of Histology and Embryology, Inonu University, Malatya, Turkey
| | - Sema Karaca Okur
- Mehmet Akif Ersoy Thoracic and Cardiovascular Surgery Training and Research Hospital, Istanbul, Turkey
| | - Seyma Acar
- Sancaktepe No. 1 Family Health Center, Istanbul, Turkey
| | - Fahri Akbas
- Faculty of Medicine, Department of Medical Biology, Bezmialem Vakif University, Istanbul, Turkey
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Manna I, Fortunato F, De Benedittis S, Sammarra I, Bertoli G, Labate A, Gambardella A. Non-Coding RNAs: New Biomarkers and Therapeutic Targets for Temporal Lobe Epilepsy. Int J Mol Sci 2022; 23:ijms23063063. [PMID: 35328484 PMCID: PMC8954985 DOI: 10.3390/ijms23063063] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/08/2022] [Accepted: 03/10/2022] [Indexed: 02/04/2023] Open
Abstract
Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy; it is considered a network disorder associated with structural changes. Incomplete knowledge of the pathological changes in TLE complicates a therapeutic approach; indeed, 30 to 50% of patients with TLE are refractory to drug treatment. Non-coding RNAs (ncRNAs), acting as epigenetic factors, participate in the regulation of the pathophysiological processes of epilepsy and are dysregulated during epileptogenesis. Abnormal expression of ncRNA is observed in patients with epilepsy and in animal models of epilepsy. Furthermore, ncRNAs could also be used as biomarkers for the diagnosis and prognosis of treatment response in epilepsy. In summary, ncRNAs can represent important mechanisms and targets for the modulation of brain excitability and can provide information on pathomechanisms, biomarkers and novel therapies for epilepsy. In this review, we summarize the latest research advances concerning mainly molecular mechanisms, regulated by ncRNA, such as synaptic plasticity, inflammation and apoptosis, already associated with the pathogenesis of TLE. Moreover, we discuss the role of ncRNAs, such as microRNAs, long non-coding RNAs and circular RNAs, in the pathophysiology of epilepsy, highlighting their use as potential biomarkers for future therapeutic approaches.
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Affiliation(s)
- Ida Manna
- Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Section of Germaneto, 88100 Catanzaro, Italy
- Correspondence: (I.M.); (A.G.)
| | - Francesco Fortunato
- Department of Medical and Surgical Sciences, Institute of Neurology, University “Magna Graecia”, Germaneto, 88100 Catanzaro, Italy; (F.F.); (S.D.B.); (I.S.); (A.L.)
| | - Selene De Benedittis
- Department of Medical and Surgical Sciences, Institute of Neurology, University “Magna Graecia”, Germaneto, 88100 Catanzaro, Italy; (F.F.); (S.D.B.); (I.S.); (A.L.)
| | - Ilaria Sammarra
- Department of Medical and Surgical Sciences, Institute of Neurology, University “Magna Graecia”, Germaneto, 88100 Catanzaro, Italy; (F.F.); (S.D.B.); (I.S.); (A.L.)
| | - Gloria Bertoli
- Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), 20090 Milan, Italy;
| | - Angelo Labate
- Department of Medical and Surgical Sciences, Institute of Neurology, University “Magna Graecia”, Germaneto, 88100 Catanzaro, Italy; (F.F.); (S.D.B.); (I.S.); (A.L.)
| | - Antonio Gambardella
- Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Section of Germaneto, 88100 Catanzaro, Italy
- Department of Medical and Surgical Sciences, Institute of Neurology, University “Magna Graecia”, Germaneto, 88100 Catanzaro, Italy; (F.F.); (S.D.B.); (I.S.); (A.L.)
- Correspondence: (I.M.); (A.G.)
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Expression Profile of miRs in Mesial Temporal Lobe Epilepsy: Systematic Review. Int J Mol Sci 2022; 23:ijms23020951. [PMID: 35055144 PMCID: PMC8781102 DOI: 10.3390/ijms23020951] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/08/2022] [Accepted: 01/12/2022] [Indexed: 02/04/2023] Open
Abstract
Temporal lobe epilepsy (TLE) is one of the most common forms of focal epilepsy in children and adults. TLE is characterized by variable onset and seizures. Moreover, this form of epilepsy is often resistant to pharmacotherapy. The search for new mechanisms for the development of TLE may provide us with a key to the development of new diagnostic methods and a personalized approach to the treatment. In recent years, the role of non-coding ribonucleic acids (RNA) has been actively studied, among which microRNA (miR) is of the greatest interest. (1) Background: The purpose of the systematic review is to analyze the studies carried out on the role of miRs in the development of mesial TLE (mTLE) and update the existing knowledge about the biomarkers of this disease. (2) Methods: The search for publications was carried out in the databases PubMed, Springer, Web of Science, Clinicalkeys, Scopus, OxfordPress, Cochrane. The search was carried out using keywords and combinations. We analyzed publications for 2016–2021, including original studies in an animal model of TLE and with the participation of patients with TLE, thematic and systemic reviews, and Cochrane reviews. (3) Results: this thematic review showed that miR‒155, miR‒153, miR‒361‒5p, miR‒4668‒5p, miR‒8071, miR‒197‒5p, miR‒145, miR‒181, miR‒199a, miR‒1183, miR‒129‒2‒3p, miR‒143‒3p (upregulation), miR–134, miR‒0067835, and miR‒153 (downregulation) can be considered as biomarkers of mTLE. However, the roles of miR‒146a, miR‒142, miR‒106b, and miR‒223 are questionable and need further study. (4) Conclusion: In the future, it will be possible to consider previously studied miRs, which have high specificity and sensitivity in mTLE, as prognostic biomarkers (predictors) of the risk of developing this disease in patients with potentially epileptogenic structural damage to the mesial regions of the temporal lobe of the brain (congenital disorders of the neuronal migration and neurogenesis, brain injury, neuro-inflammation, tumor, impaired blood supply, neurodegeneration, etc.).
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Penning A, Tosoni G, Abiega O, Bielefeld P, Gasperini C, De Pietri Tonelli D, Fitzsimons CP, Salta E. Adult Neural Stem Cell Regulation by Small Non-coding RNAs: Physiological Significance and Pathological Implications. Front Cell Neurosci 2022; 15:781434. [PMID: 35058752 PMCID: PMC8764185 DOI: 10.3389/fncel.2021.781434] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/09/2021] [Indexed: 01/11/2023] Open
Abstract
The adult neurogenic niches are complex multicellular systems, receiving regulatory input from a multitude of intracellular, juxtacrine, and paracrine signals and biological pathways. Within the niches, adult neural stem cells (aNSCs) generate astrocytic and neuronal progeny, with the latter predominating in physiological conditions. The new neurons generated from this neurogenic process are functionally linked to memory, cognition, and mood regulation, while much less is known about the functional contribution of aNSC-derived newborn astrocytes and adult-born oligodendrocytes. Accumulating evidence suggests that the deregulation of aNSCs and their progeny can impact, or can be impacted by, aging and several brain pathologies, including neurodevelopmental and mood disorders, neurodegenerative diseases, and also by insults, such as epileptic seizures, stroke, or traumatic brain injury. Hence, understanding the regulatory underpinnings of aNSC activation, differentiation, and fate commitment could help identify novel therapeutic avenues for a series of pathological conditions. Over the last two decades, small non-coding RNAs (sncRNAs) have emerged as key regulators of NSC fate determination in the adult neurogenic niches. In this review, we synthesize prior knowledge on how sncRNAs, such as microRNAs (miRNAs) and piwi-interacting RNAs (piRNAs), may impact NSC fate determination in the adult brain and we critically assess the functional significance of these events. We discuss the concepts that emerge from these examples and how they could be used to provide a framework for considering aNSC (de)regulation in the pathogenesis and treatment of neurological diseases.
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Affiliation(s)
- Amber Penning
- Laboratory of Neurogenesis and Neurodegeneration, Netherlands Institute for Neuroscience, Amsterdam, Netherlands
| | - Giorgia Tosoni
- Laboratory of Neurogenesis and Neurodegeneration, Netherlands Institute for Neuroscience, Amsterdam, Netherlands
| | - Oihane Abiega
- Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, Netherlands
| | - Pascal Bielefeld
- Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, Netherlands
| | - Caterina Gasperini
- Neurobiology of miRNAs Lab, Istituto Italiano di Tecnologia, Genova, Italy
| | | | - Carlos P. Fitzsimons
- Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, Netherlands
| | - Evgenia Salta
- Laboratory of Neurogenesis and Neurodegeneration, Netherlands Institute for Neuroscience, Amsterdam, Netherlands
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Huang H, Cui G, Tang H, Kong L, Wang X, Cui C, Xiao Q, Ji H. Relationships between plasma expression levels of microRNA-146a and microRNA-132 in epileptic patients and their cognitive, mental and psychological disorders. Bioengineered 2022; 13:941-949. [PMID: 34969353 PMCID: PMC8805917 DOI: 10.1080/21655979.2021.2015528] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
We aimed to explore the relationships between the plasma expression levels of microRNA (miR)-146a and miR-132 in epileptic patients and cognitive, mental and psychological disorders. Eighty epileptic patients and seventy healthy subjects as controls were evaluated with Montreal Cognitive Assessment (MoCA), Hamilton Anxiety Rating (HAMA) and Hamilton Depression Rating (HAMD) scales, and plasma samples were collected. MiR-146a and miR-132 levels were detected by real-time quantitative PCR. The total incidence rate of cognitive dysfunction, anxiety and depression in epilepsy group was 62.5%. Cognitive dysfunction was correlated positively with educational level, but negatively with disease course, duration and type of administration. The frequency and duration of seizures were positively correlated with anxiety. Depression was correlated negatively with educational level, whereas positively with course of disease and number of used drugs. Epileptic patients had significantly higher miR-146a and miR-132 levels than those of healthy controls. The miR-146a and miR-132 levels of patients with complications were significantly higher than those of cases without complications. Their expressions were correlated negatively with total MoCA scale score, but positively with type of complications. MiR-132 expression was positively correlated with the total scores of HAMA and HAMD scales. Plasma miR-146a and miR-132 expressions increased in epileptic patients, and miR-132 expression reflected the severity of epilepsy and predicted the risks of complications.
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Affiliation(s)
- Hui Huang
- Department of Neurology, Huaibei People's Hospital, Huaibei, P. R. China
| | - Guiyun Cui
- Epilepsy Center, Affiliated Hospital of Xuzhou Medical University, Xuzhou, P. R. China
| | - Hai Tang
- Epilepsy Center, Affiliated Hospital of Xuzhou Medical University, Xuzhou, P. R. China
| | - Lingwen Kong
- Epilepsy Center, Affiliated Hospital of Xuzhou Medical University, Xuzhou, P. R. China
| | - Xiaopeng Wang
- Epilepsy Center, Affiliated Hospital of Xuzhou Medical University, Xuzhou, P. R. China
| | - Chenchen Cui
- Epilepsy Center, Affiliated Hospital of Xuzhou Medical University, Xuzhou, P. R. China
| | - Qihua Xiao
- Epilepsy Center, Affiliated Hospital of Xuzhou Medical University, Xuzhou, P. R. China
| | - Huiming Ji
- Medical Laboratory, Affiliated Hospital of Xuzhou Medical University, Xuzhou, P. R. China
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Bonilla-Jaime H, Zeleke H, Rojas A, Espinosa-Garcia C. Sleep Disruption Worsens Seizures: Neuroinflammation as a Potential Mechanistic Link. Int J Mol Sci 2021; 22:12531. [PMID: 34830412 PMCID: PMC8617844 DOI: 10.3390/ijms222212531] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 11/16/2021] [Accepted: 11/18/2021] [Indexed: 12/13/2022] Open
Abstract
Sleep disturbances, such as insomnia, obstructive sleep apnea, and daytime sleepiness, are common in people diagnosed with epilepsy. These disturbances can be attributed to nocturnal seizures, psychosocial factors, and/or the use of anti-epileptic drugs with sleep-modifying side effects. Epilepsy patients with poor sleep quality have intensified seizure frequency and disease progression compared to their well-rested counterparts. A better understanding of the complex relationship between sleep and epilepsy is needed, since approximately 20% of seizures and more than 90% of sudden unexpected deaths in epilepsy occur during sleep. Emerging studies suggest that neuroinflammation, (e.g., the CNS immune response characterized by the change in expression of inflammatory mediators and glial activation) may be a potential link between sleep deprivation and seizures. Here, we review the mechanisms by which sleep deprivation induces neuroinflammation and propose that neuroinflammation synergizes with seizure activity to worsen neurodegeneration in the epileptic brain. Additionally, we highlight the relevance of sleep interventions, often overlooked by physicians, to manage seizures, prevent epilepsy-related mortality, and improve quality of life.
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Affiliation(s)
- Herlinda Bonilla-Jaime
- Departamento de Biología de la Reproducción, Área de Biología Conductual y Reproductiva, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de Mexico CP 09340, Mexico;
| | - Helena Zeleke
- Neuroscience and Behavioral Biology Program, College of Arts and Sciences, Emory University, Atlanta, GA 30322, USA;
| | - Asheebo Rojas
- Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA 30322, USA
| | - Claudia Espinosa-Garcia
- Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA 30322, USA
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Identification and Validation of a Dysregulated miRNA-Associated mRNA Network in Temporal Lobe Epilepsy. BIOMED RESEARCH INTERNATIONAL 2021; 2021:4118216. [PMID: 34722763 PMCID: PMC8556104 DOI: 10.1155/2021/4118216] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 09/26/2021] [Accepted: 09/28/2021] [Indexed: 01/26/2023]
Abstract
Objectives This study is aimed at exploring the relationships between miRNAs and mRNAs and to characterize their biological functions in temporal lobe epilepsy (TLE). Methods Novel clinical significant miRNAs and target genes and their potential underlying mechanisms have been discovered and explored by mining miRNAs and mRNA expression data of TLE patients using various bioinformatics methods. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to validate the bioinformatic analysis results. Results A total of 6 dysregulated miRNAs and 442 differentially expressed genes (DEGs) related to TLE were obtained from GEO database (GSE114701 and GSE127871 datasets). A protein-protein interaction (PPI) network containing the 442 DEGs was established. mRNA response elements from the 6 dysregulated miRNAs were predicted using the miRDB and TargetScan bioinformatic tools. By merging the identified targets of the dysregulated miRNAs and the 247 downregulated DEGs, a miRNA-mRNA network was constructed revealing the interaction of miR-484 with eight mRNAs (ABLIM2, CEP170B, CTD-3193O13.9, EFNA5, GAP43, PRKCB, FXYD7, and NCAN). A weighted correlation network analysis (WGCNA) based on the eight genes was established and demonstrated that these mRNAs, except FXYD7 and NCAN, were hub genes in the network. Gene Oncology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that the six hub genes were mainly involved in cellular-related biological functions and the neurotransmitter synapse pathway. The differences in expression levels of the miR-484 and the three hub genes (CTD-3193O13.9, EFNA5, and PRKCB) observed experimentally in TLE patients compared to those of healthy controls were consistent with the WGCNA prediction. Conclusion Our study suggests that understanding the miRNA-mRNA interactions will provide insights into the epilepsy pathogenesis. In addition, our results indicate that miR-484 may be a promising novel biomarker for TLE.
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Bandopadhyay R, Singh T, Ghoneim MM, Alshehri S, Angelopoulou E, Paudel YN, Piperi C, Ahmad J, Alhakamy NA, Alfaleh MA, Mishra A. Recent Developments in Diagnosis of Epilepsy: Scope of MicroRNA and Technological Advancements. BIOLOGY 2021; 10:1097. [PMID: 34827090 PMCID: PMC8615191 DOI: 10.3390/biology10111097] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/21/2021] [Accepted: 10/21/2021] [Indexed: 12/18/2022]
Abstract
Epilepsy is one of the most common neurological disorders, characterized by recurrent seizures, resulting from abnormally synchronized episodic neuronal discharges. Around 70 million people worldwide are suffering from epilepsy. The available antiepileptic medications are capable of controlling seizures in around 60-70% of patients, while the rest remain refractory. Poor seizure control is often associated with neuro-psychiatric comorbidities, mainly including memory impairment, depression, psychosis, neurodegeneration, motor impairment, neuroendocrine dysfunction, etc., resulting in poor prognosis. Effective treatment relies on early and correct detection of epileptic foci. Although there are currently a few well-established diagnostic techniques for epilepsy, they lack accuracy and cannot be applied to patients who are unsupportive or harbor metallic implants. Since a single test result from one of these techniques does not provide complete information about the epileptic foci, it is necessary to develop novel diagnostic tools. Herein, we provide a comprehensive overview of the current diagnostic tools of epilepsy, including electroencephalography (EEG) as well as structural and functional neuroimaging. We further discuss recent trends and advances in the diagnosis of epilepsy that will enable more effective diagnosis and clinical management of patients.
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Affiliation(s)
- Ritam Bandopadhyay
- Department of Pharmacology, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India;
| | - Tanveer Singh
- Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA;
| | - Mohammed M. Ghoneim
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia;
| | - Sultan Alshehri
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Efthalia Angelopoulou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.A.); (C.P.)
| | - Yam Nath Paudel
- Neuropharmacology Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Subang Jaya 47500, Selangor, Malaysia;
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.A.); (C.P.)
| | - Javed Ahmad
- Department of Pharmaceutics, College of Pharmacy, Najran University, Najran 11001, Saudi Arabia;
| | - Nabil A. Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (M.A.A.)
| | - Mohamed A. Alfaleh
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (M.A.A.)
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Awanish Mishra
- Department of Pharmacology, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India;
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)—Guwahati, Changsari, Guwahati 781101, Assam, India
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Fu M, Zhu Y, Zhang J, Wu W, Sun Y, Zhang X, Tao J, Li Z. MicroRNA-221-3p Suppresses the Microglia Activation and Seizures by Inhibiting of HIF-1α in Valproic Acid-Resistant Epilepsy. Front Pharmacol 2021; 12:714556. [PMID: 34497517 PMCID: PMC8419275 DOI: 10.3389/fphar.2021.714556] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/10/2021] [Indexed: 01/20/2023] Open
Abstract
One-third of patients with epilepsy suffer from drug-resistant epilepsy (DRE). Valproic acid (VPA) is a classic anticonvulsant drug, and its resistance is a crucial predictor of DRE, but the pathogenesis remain unknown. Most patients with VPA-resistant epilepsy appear distinct inflammatory response and local hypoxia. Hypoxia-inducible factor (HIF)-1α is an essential effector molecule of hypoxia and inflammation, and may exert therefore a significant effect on the development of VPA-resistant epilepsy. We systematically assess the significance of HIF-1α on children and mice with VPA-resistant epilepsy, and investigated the micro (mi) RNAs that regulate HIF-1α expression. We established models of VPA-sensitive epilepsy and VPA-resistant epilepsy in mice, and confirmed that they had significant differences in epileptic behavior and electroencephalography data. Through proteomics analysis, we identified that HIF-1α was overexpressed in mice with VPA-resistant epilepsy, and regulated the expression of interleukin-1β and tumor necrosis factor-α. Increased expression of HIF-1α led to the increase of microglia and induced their polarization from the M2 phenotype to M1 phenotype, which triggered the release of proinflammatory mediators. Bioinformatics analysis of public databases demonstrated that miR-221-3p was reduced in VPA-resistant epilepsy, and negatively regulated HIF-1α expression. Intervention using miR-221-3p mimics reduced HIF-1α expression markedly and suppressed the activation of microglia and the release of inflammatory mediators, which relieved epileptic seizures of VPA-resistant epilepsy. These observations reveal miR-221-3p/HIF-1α as essential component in pathogenesis of VPA-resistant epilepsy which represent therapeutic antiseizure targets.
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Affiliation(s)
- Meng Fu
- Department of Clinical Pharmacy, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Yiqing Zhu
- Department of Clinical Pharmacy, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Junqi Zhang
- Department of Clinical Pharmacy, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Wei Wu
- Department of Clinical Pharmacy, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Yunxia Sun
- Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xuemei Zhang
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Jie Tao
- Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhiping Li
- Department of Clinical Pharmacy, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
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Bruxel EM, do Canto AM, Bruno DCF, Geraldis JC, Lopes-Cendes I. Multi-omic strategies applied to the study of pharmacoresistance in mesial temporal lobe epilepsy. Epilepsia Open 2021; 7 Suppl 1:S94-S120. [PMID: 34486831 PMCID: PMC9340306 DOI: 10.1002/epi4.12536] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 08/18/2021] [Accepted: 08/20/2021] [Indexed: 12/19/2022] Open
Abstract
Mesial temporal lobe epilepsy (MTLE) is the most common type of focal epilepsy in adults, and hippocampal sclerosis (HS) is a frequent histopathological feature in patients with MTLE. Pharmacoresistance is present in at least one-third of patients with MTLE with HS (MTLE+HS). Several hypotheses have been proposed to explain the mechanisms of pharmacoresistance in epilepsy, including the effect of genetic and molecular factors. In recent years, the increased knowledge generated by high-throughput omic technologies has significantly improved the power of molecular genetic studies to discover new mechanisms leading to disease and response to treatment. In this review, we present and discuss the contribution of different omic modalities to understand the basic mechanisms determining pharmacoresistance in patients with MTLE+HS. We provide an overview and a critical discussion of the findings, limitations, new approaches, and future directions of these studies to improve the understanding of pharmacoresistance in MTLE+HS. However, it is important to point out that, as with other complex traits, pharmacoresistance to anti-seizure medications is likely a multifactorial condition in which gene-gene and gene-environment interactions play an important role. Thus, studies using multidimensional approaches are more likely to unravel these intricate biological processes.
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Affiliation(s)
- Estela M Bruxel
- Departments of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.,Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, Brazil
| | - Amanda M do Canto
- Departments of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.,Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, Brazil
| | - Danielle C F Bruno
- Departments of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.,Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, Brazil
| | - Jaqueline C Geraldis
- Departments of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.,Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, Brazil
| | - Iscia Lopes-Cendes
- Departments of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.,Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, Brazil
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Ammal Kaidery N, Ahuja M, Sharma SM, Thomas B. An Emerging Role of miRNAs in Neurodegenerative Diseases: Mechanisms and Perspectives on miR146a. Antioxid Redox Signal 2021; 35:580-594. [PMID: 33403895 PMCID: PMC8388248 DOI: 10.1089/ars.2020.8256] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Significance: Advancements in and access to health care have led to unprecedented improvements in the quality of life and increased lifespan of human beings in the past century. However, aging is a significant risk factor for neurodegenerative diseases (NDs). Hence, improved life expectancy has led to an increased incidence of NDs. Despite intense research, effective treatments for NDs remain elusive. The future of neurotherapeutics development depends on effective disease modification strategies centered on carefully scrutinized targets. Recent Advances: As a promising new direction, recent evidence has demonstrated that epigenetic processes modify diverse biochemical pathways, including those related to NDs. Small non-coding RNAs, known as microRNAs (miRNAs), are components of the epigenetic system that alter the expression of target genes at the post-transcriptional level. Critical Issues: miRNAs are expressed abundantly in the central nervous system and are critical for the normal functioning and survival of neurons. Here, we review recent advances in elucidating miRNAs' roles in NDs and discuss their potential as therapeutic targets. In particular, neuroinflammation is a major pathological hallmark of NDs and miR146a is a crucial regulator of inflammation. Future Directions: Finally, we explore the possibilities of developing miR146a as a potential biomarker and therapeutic target where additional research may help facilitate the detection and amelioration of neuroinflammation in NDs. Antioxid. Redox Signal. 35, 580-594.
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Affiliation(s)
- Navneet Ammal Kaidery
- Darby Children's Research Institute, Departments of Medical University of South Carolina, Charleston, South Carolina, USA.,Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Manuj Ahuja
- Darby Children's Research Institute, Departments of Medical University of South Carolina, Charleston, South Carolina, USA.,Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Sudarshana M Sharma
- Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA.,Hollings Cancer Center, and Departments of Medical University of South Carolina, Charleston, South Carolina, USA
| | - Bobby Thomas
- Darby Children's Research Institute, Departments of Medical University of South Carolina, Charleston, South Carolina, USA.,Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA.,Neuroscience, Medical University of South Carolina, Charleston, South Carolina, USA.,Drug Discovery, Medical University of South Carolina, Charleston, South Carolina, USA
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Guan X, Zhang Y, Gareev I, Beylerli O, Li X, Lu G, Lv L, Hai X. MiR-499a prevents astrocytes mediated inflammation in ischemic stroke by targeting PTEN. Noncoding RNA Res 2021; 6:146-152. [PMID: 34632168 PMCID: PMC8488463 DOI: 10.1016/j.ncrna.2021.09.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 09/24/2021] [Accepted: 09/24/2021] [Indexed: 01/29/2023] Open
Abstract
INTRODUCTION Ischemic stroke (IS) is a common and severe neurological disorder and is associated with high rates of mortality and morbidity. Inflammatory reaction in astrocytes is one of the important pathological factors of stroke. Improved understanding of the underlying molecular mechanisms should aid better treatment of the disease. This study aimed to test our hypothesis that a miR-499a played an important role in the inflammatory response in astrocytes induced by IS targeting phosphatase and tensin homologue deleted on chromosome 10 (PTEN). METHODS This study was comprised of two models: oxygen-glucose deprivation (OGD) and reoxygenation model. Quantitative real-time PCR (qRT-PCR) and Western blot were used to examine gene expression levels, and MTT assay analysis were used to examine cell states. The relationships between miR-499a and PTEN were confirmed by luciferase reporter assay. RESULTS MiR-499a was robustly downregulated with OGD induced injury in astrocytes. Forced transient expression of miR-499a in OGD astrocytes nearly completely reversed the inflammatory response. Knockdown of miR-499a by its specific inhibitor in healthy astrocytes induced the inflammatory response resembling those produced by OGD. On the other hand, PTEN was markedly upregulated in OGD astrocytes, which was reciprocal to the expression of miR-499a. PTEN was experimentally validated as a direct target gene for miR-499a. Overexpression of PTEN was able to induce an inflammatory response of astrocytes. Moreover, PTEN siRNA counteracted the inflammatory response induced by OGD. CONCLUSIONS Taken together, our findings indicate miR-499a as an important factor to prevent inflammatory response and suggest miR-499a as a new molecule for the treatment of IS. The present study also demonstrated the relationship between miR-499a and PTEN, with PTEN as a downstream signaling mediator of miR-499a in the inflammatory response of astrocytes induced by IS.
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Affiliation(s)
- Xiaoxiang Guan
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang, 150001, PR China
| | - Yiwei Zhang
- Harbin Medical University, 157 Baojian Street, Harbin, Heilongjiang, 150001, PR China
| | - Ilgiz Gareev
- Bashkir State Medical University, Ufa, 450008, Russia
| | - Ozal Beylerli
- Bashkir State Medical University, Ufa, 450008, Russia
| | - Xinyuan Li
- The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang, 150001, PR China
| | - Guitian Lu
- The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang, 150001, PR China
| | - Lin Lv
- The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang, 150001, PR China
| | - Xin Hai
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang, 150001, PR China
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Jauhari A, Singh T, Mishra S, Shankar J, Yadav S. Coordinated Action of miR-146a and Parkin Gene Regulate Rotenone-induced Neurodegeneration. Toxicol Sci 2021; 176:433-445. [PMID: 32392329 DOI: 10.1093/toxsci/kfaa066] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Mitochondrial dysfunction is a common cause in pathophysiology of different neurodegenerative diseases. Elimination of dysfunctional and damaged mitochondria is a key requirement for maintaining homeostasis and bioenergetics of degenerating neurons. Using global microRNA (miRNA) profiling in a systemic rotenone model of Parkinson's disease, we have identified miR-146a as upmost-regulated miRNA, which is known as inflammation regulatory miRNA. Here, we report the role of activated nuclear factor kappa beta (NF-kβ) in miR-146a-mediated downregulation of Parkin protein, which inhibits clearance of damaged mitochondria and induces neurodegeneration. Our studies have shown that 4-week rotenone exposure (2.5 mg/kg b.wt) induced oxidative imbalance-mediated NF-kβ activation in 1-year-old rat's brain. Activated NF-kβ binds in promoter region of miR-146a gene and induces its transcription, which downregulates levels of Parkin protein. Decreased amount of Parkin protein results in accumulation of damaged and dysfunctional mitochondria, which further promotes the generation of reactive oxygen species in degenerating neurons. In conclusion, our studies have identified direct role of NF-kβ-mediated upregulation of miR-146a in regulating mitophagy through inhibition of the Parkin gene.
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Affiliation(s)
- Abhishek Jauhari
- Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow 226001, Uttar Pradesh, India.,Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, New Delhi, India.,Department of Neurological Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Tanisha Singh
- Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow 226001, Uttar Pradesh, India.,Department of Neurological Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Saumya Mishra
- Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow 226001, Uttar Pradesh, India.,Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, New Delhi, India
| | - Jai Shankar
- Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow 226001, Uttar Pradesh, India
| | - Sanjay Yadav
- Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow 226001, Uttar Pradesh, India.,Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, New Delhi, India.,Department of Biochemistry, All India Institute of Medical Sciences, Raebareli-229405, Uttar Pradesh, India
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Zummo L, Vitale AM, Caruso Bavisotto C, De Curtis M, Garbelli R, Giallonardo AT, Di Bonaventura C, Fanella M, Conway de Macario E, Cappello F, Macario AJL, Marino Gammazza A. Molecular Chaperones and miRNAs in Epilepsy: Pathogenic Implications and Therapeutic Prospects. Int J Mol Sci 2021; 22:ijms22168601. [PMID: 34445306 PMCID: PMC8395327 DOI: 10.3390/ijms22168601] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 08/05/2021] [Accepted: 08/06/2021] [Indexed: 11/16/2022] Open
Abstract
Epilepsy is a pathologic condition with high prevalence and devastating consequences for the patient and its entourage. Means for accurate diagnosis of type, patient monitoring for predicting seizures and follow up, and efficacious treatment are desperately needed. To improve this adverse outcome, miRNAs and the chaperone system (CS) are promising targets to understand pathogenic mechanisms and for developing theranostics applications. miRNAs implicated in conditions known or suspected to favor seizures such as neuroinflammation, to promote epileptic tolerance and neuronal survival, to regulate seizures, and others showing variations in expression levels related to seizures are promising candidates as useful biomarkers for diagnosis and patient monitoring, and as targets for developing novel therapies. Components of the CS are also promising as biomarkers and as therapeutic targets, since they participate in epileptogenic pathways and in cytoprotective mechanisms in various epileptogenic brain areas, even if what they do and how is not yet clear. The data in this review should help in the identification of molecular targets among the discussed miRNAs and CS components for research aiming at understanding epileptogenic mechanisms and, subsequently, develop means for predicting/preventing seizures and treating the disease.
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Affiliation(s)
- Leila Zummo
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, Section of Human Anatomy, University of Palermo, 90127 Palermo, Italy; (L.Z.); (A.M.V.); (C.C.B.); (F.C.)
- Department of Neurology and Stroke Unit, A.R.N.A.S. Ospedale Civico—Di Cristina Benfratelli, 90127 Palermo, Italy
| | - Alessandra Maria Vitale
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, Section of Human Anatomy, University of Palermo, 90127 Palermo, Italy; (L.Z.); (A.M.V.); (C.C.B.); (F.C.)
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy;
| | - Celeste Caruso Bavisotto
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, Section of Human Anatomy, University of Palermo, 90127 Palermo, Italy; (L.Z.); (A.M.V.); (C.C.B.); (F.C.)
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy;
| | - Marco De Curtis
- Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (M.D.C.); (R.G.)
| | - Rita Garbelli
- Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (M.D.C.); (R.G.)
| | - Anna Teresa Giallonardo
- Department of Human Neurosciences “Sapienza”, University of Rome, 00185 Rome, Italy; (A.T.G.); (C.D.B.); (M.F.)
- Policlinico Umberto I, 00161 Rome, Italy
| | - Carlo Di Bonaventura
- Department of Human Neurosciences “Sapienza”, University of Rome, 00185 Rome, Italy; (A.T.G.); (C.D.B.); (M.F.)
- Policlinico Umberto I, 00161 Rome, Italy
| | - Martina Fanella
- Department of Human Neurosciences “Sapienza”, University of Rome, 00185 Rome, Italy; (A.T.G.); (C.D.B.); (M.F.)
- Policlinico Umberto I, 00161 Rome, Italy
| | - Everly Conway de Macario
- Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD 21202, USA;
| | - Francesco Cappello
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, Section of Human Anatomy, University of Palermo, 90127 Palermo, Italy; (L.Z.); (A.M.V.); (C.C.B.); (F.C.)
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy;
| | - Alberto J. L. Macario
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy;
- Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD 21202, USA;
| | - Antonella Marino Gammazza
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, Section of Human Anatomy, University of Palermo, 90127 Palermo, Italy; (L.Z.); (A.M.V.); (C.C.B.); (F.C.)
- Correspondence:
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Multi-omics in mesial temporal lobe epilepsy with hippocampal sclerosis: Clues into the underlying mechanisms leading to disease. Seizure 2021; 90:34-50. [DOI: 10.1016/j.seizure.2021.03.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 02/26/2021] [Accepted: 03/02/2021] [Indexed: 02/07/2023] Open
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Nasirishargh A, Kumar P, Ramasubramanian L, Clark K, Hao D, Lazar SV, Wang A. Exosomal microRNAs from mesenchymal stem/stromal cells: Biology and applications in neuroprotection. World J Stem Cells 2021; 13:776-794. [PMID: 34367477 PMCID: PMC8316862 DOI: 10.4252/wjsc.v13.i7.776] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/29/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are extensively studied as cell-therapy agents for neurological diseases. Recent studies consider exosomes secreted by MSCs as important mediators for MSCs' neuroprotective functions. Exosomes transfer functional molecules including proteins, lipids, metabolites, DNAs, and coding and non-coding RNAs from MSCs to their target cells. Emerging evidence shows that exosomal microRNAs (miRNAs) play a key role in the neuroprotective properties of these exosomes by targeting several genes and regulating various biological processes. Multiple exosomal miRNAs have been identified to have neuroprotective effects by promoting neurogenesis, neurite remodeling and survival, and neuroplasticity. Thus, exosomal miRNAs have significant therapeutic potential for neurological disorders such as stroke, traumatic brain injury, and neuroinflammatory or neurodegenerative diseases and disorders. This review discusses the neuroprotective effects of selected miRNAs (miR-21, miR-17-92, miR-133, miR-138, miR-124, miR-30, miR146a, and miR-29b) and explores their mechanisms of action and applications for the treatment of various neurological disease and disorders. It also provides an overview of state-of-the-art bioengineering approaches for isolating exosomes, optimizing their yield and manipulating the miRNA content of their cargo to improve their therapeutic potential.
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Affiliation(s)
- Aida Nasirishargh
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
| | - Priyadarsini Kumar
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
| | - Lalithasri Ramasubramanian
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, United States
| | - Kaitlin Clark
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
| | - Dake Hao
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
| | - Sabrina V Lazar
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
| | - Aijun Wang
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
- Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, United States.
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47
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Weng N, Sun J, Kuang S, Lan H, He Q, Yang H, Zhang L, Xue H. MicroRNA-451 Aggravates Kainic Acid-induced Seizure and Neuronal Apoptosis by Targeting GDNF. Curr Neurovasc Res 2021; 17:50-57. [PMID: 31870266 DOI: 10.2174/1567202617666191223150510] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 11/12/2019] [Accepted: 11/24/2019] [Indexed: 11/22/2022]
Abstract
AIM Epilepsy is a common and serious neurological disease that causes recurrent episodes, but its molecular mechanism remains unclear. Abnormal miRNA expression is associated with epilepsy, including miR-451. This research investigated the role of miR-451 in seizure and its detailed mechanism. METHODS The seizure mice model was induced by kainic acid (KA) injection to the right lateral cerebral ventricle. Behavioral changes in mice were observed and evaluated by the Racine Scale. The miR-451 knockout mice were established by adenovirus infection. The in vitro model was performed by miR-451 mimics transfected HEK-293 cells. The amount of neuronal death and morphological changes were evaluated by Nissl staining and H&E staining. RESULTS The results showed that miR-451 is up regulated in KA-induced seizure models and miR- 451 knockout decreased the behavior score and improved the pathological changes of the hippocampus. Besides, MiR-451 knockout inhibited the apoptosis of hippocampal neurons. Bioinformatics studies have shown that glial cell line-derived neurotrophic factor (GDNF) is a target gene of miR-451. MiR-451 could negatively regulate the expression of GDNF. GDNF overexpression could reverse the effect of miR-451 on KA induced brain injury and neuronal apoptosis. CONCLUSION This research demonstrates that miR-451 can affect the behavior of KA-induced epilepsy mice and hippocampal neuronal damage by regulating GDNF expression. The results would provide an experimental foundation for further research about the potential contribution of mi- RNAs to epilepsy pathophysiology.
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Affiliation(s)
- Ning Weng
- The Second Clinical College of Guangzhou, University of Chinese Medicine, Guangzhou City, Guangdong Province, 510120, China.,Department of Neurology, The Second Affiliated Hospital of Guizhou, Guizhou University of Traditional Chinese Medicine, Guiyang City, Guizhou Province, 550003, China
| | - Jingbo Sun
- The Second Clinical College of Guangzhou, University of Chinese Medicine, Guangzhou City, Guangdong Province, 510120, China
| | - Shixiang Kuang
- Department of Neurology, The Second Affiliated Hospital of Guizhou, Guizhou University of Traditional Chinese Medicine, Guiyang City, Guizhou Province, 550003, China
| | - Hai Lan
- Department of Hematology, No.1 Affiliated Hospital of Guangzhou, Guangzhou University of Chinese Medicine, Guangzhou City, Guangdong Province, 510405, China
| | - Qiansong He
- Department of Neurology, The Second Clinical College of Guizhou, Guizhou University of Traditional Chinese Medicine, Guiyang City, Guizhou Province, 550003, China
| | - Hui Yang
- Department of Neurology, The Second Clinical College of Guizhou, Guizhou University of Traditional Chinese Medicine, Guiyang City, Guizhou Province, 550003, China
| | - Lin Zhang
- Department of Neurology, The Second Affiliated Hospital of Guizhou, Guizhou University of Traditional Chinese Medicine, Guiyang City, Guizhou Province, 550003, China
| | - Hong Xue
- Department of Neurology, The Second Affiliated Hospital of Guizhou, Guizhou University of Traditional Chinese Medicine, Guiyang City, Guizhou Province, 550003, China.,Department of Neurology, The Second Clinical College of Guizhou, Guizhou University of Traditional Chinese Medicine, Guiyang City, Guizhou Province, 550003, China
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48
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Aslani M, Mortazavi-Jahromi SS, Mirshafiey A. Efficient roles of miR-146a in cellular and molecular mechanisms of neuroinflammatory disorders: An effectual review in neuroimmunology. Immunol Lett 2021; 238:1-20. [PMID: 34293378 DOI: 10.1016/j.imlet.2021.07.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 07/03/2021] [Accepted: 07/15/2021] [Indexed: 12/16/2022]
Abstract
Known as one of the most sophisticated systems of the human body, the nervous system consists of neural cells and controls all parts of the body. It is closely related to the immune system. The effects of inflammation and immune reactions have been observed in the pathogenesis of some neurological disorders. Defined as the gene expression regulators, miRNAs participate in cellular processes. miR-146a is a mediator in the neuroimmune system, leaving substantial effects on the homeostasis of immune and brain cells, neuronal identities acquisition, and immune responses regulation in the nervous system. Its positive efficiency has been proven in modulating inflammatory reactions, hemorrhagic complications, and pain. Moreover, the miR-146a targets play a key role in the pathogenesis of these illnesses. Based on the performance of its targets, miR-146a can have various effects on the disease progress. The abnormal expression/function of miR-146a has been reported in neuroinflammatory disorders. There is research evidence that this molecule qualifies as a desirable biomarker for some disorders and can even be a therapeutic target. This study aims to provide a meticulous review regarding the roles of miR-146a in the pathogenesis and progression of several neuroinflammatory disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, temporal lobe epilepsy, ischemic stroke, etc. The study also considers its eligibility for use as an ideal biomarker and therapeutic target in these diseases. The awareness of these mechanisms can facilitate the disease management/treatment, lead to patients' amelioration, improve the quality of life, and mitigate the risk of death.
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Affiliation(s)
- Mona Aslani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Abbas Mirshafiey
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
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49
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Wang GY, Luan ZL, Che NW, Yan DB, Sun XW, Zhang C, Yin J. Inhibition of microRNA-129-2-3p protects against refractory temporal lobe epilepsy by regulating GABRA1. Brain Behav 2021; 11:e02195. [PMID: 34029007 PMCID: PMC8323041 DOI: 10.1002/brb3.2195] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 03/30/2021] [Accepted: 05/05/2021] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Accumulating evidence demonstrates that certain microRNAs play critical roles in epileptogenesis. Our previous studies found microRNA (miR)-129-2-3p was induced in patients with refractory temporal lobe epilepsy (TLE). In this study, we aimed to explore the role of miR-129-2-3p in TLE pathogenesis. METHOD By bioinformatics, we predicted miR-129-2-3p may target the gene GABRA1 encoding the GABA type A receptor subunit alpha 1. Luciferase assay was used to investigate the regulation of miR-129-2-3p on GABRA1 3'UTR. The dynamic expression of miR-129-2-3p and GABRA1 mRNA and protein levels were measured in primary hippocampal neurons and a rat kainic acid (KA)-induced seizure model by quantitative reverse transcription-polymerase chain reaction (qPCR), Western blotting, and immunostaining. MiR-129-2-3p agomir and antagomir were utilized to explore their role in determining GABRA1 expression. The effects of targeting miR-129-2-3p and GABRA1 on epilepsy were assessed by electroencephalography (EEG) and immunostaining. RESULTS Luciferase assay, qPCR, and Western blot results suggested GABRA1 as a direct target of miR-129-2-3p. MiR-129-2-3p level was significantly upregulated, whereas GABRA1 expression downregulated in KA-treated rat primary hippocampal neurons and KA-induced seizure model. In vivo knockdown of miR-129-2-3p by antagomir alleviated the seizure-like EEG findings in accordance with the upregulation of GABRA1. Furthermore, the seizure-suppressing effect of the antagomir was partly GABRA1 dependent. CONCLUSIONS The results suggested GABRA1 as a target of miR-129-2-3p in rat primary hippocampal neurons and a rat kainic acid (KA) seizure model. Silencing of miR-129-2-3p exerted a seizure-suppressing effect in rats. MiR-129-2-3p/GABRA1 pathway may represent a potential target for the prevention and treatment of refractory epilepsy.
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Affiliation(s)
- Guan-Yu Wang
- Department of Neurosurgery, the Second Affiliated Hospital of Dalian Medical University, Dalian, China.,Epileptic Center of Liaoning, the Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhi-Lin Luan
- Department of Neurosurgery, the Second Affiliated Hospital of Dalian Medical University, Dalian, China.,Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
| | - Ning-Wei Che
- Department of Neurosurgery, the Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - De-Bin Yan
- Department of Neurosurgery, the Second Affiliated Hospital of Dalian Medical University, Dalian, China.,Epileptic Center of Liaoning, the Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiao-Wan Sun
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
| | - Cong Zhang
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
| | - Jian Yin
- Department of Neurosurgery, the Second Affiliated Hospital of Dalian Medical University, Dalian, China.,Epileptic Center of Liaoning, the Second Affiliated Hospital of Dalian Medical University, Dalian, China
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50
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Bencurova P, Baloun J, Hynst J, Oppelt J, Kubova H, Pospisilova S, Brazdil M. Dynamic miRNA changes during the process of epileptogenesis in an infantile and adult-onset model. Sci Rep 2021; 11:9649. [PMID: 33958654 PMCID: PMC8102630 DOI: 10.1038/s41598-021-89084-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 04/12/2021] [Indexed: 02/03/2023] Open
Abstract
Temporal lobe epilepsy (TLE) is the most common epilepsy type. TLE onset in infancy aggravates features like severity, drug responsiveness, or development of comorbidities. These aggravations may arise from altered micro RNA (miRNA) expression specific to the early onset of the disease. Although the miRNA involvement in TLE is widely studied, the relationship between the onset-age and miRNA expression has not been addressed. Here, we investigated the miRNA profile of infantile and adult-onset TLE in rats combining sequencing and PCR. Since miRNA expression changes with the disease progression, we scrutinized miRNA dynamics across three stages: acute, latent, and chronic. We report that infantile-onset TLE leads to changes in the expression of fewer miRNAs across these stages. Interestingly, the miRNA profile in the acute stage of infantile-onset TLE overlaps in dysregulation of miR-132-5p, -205, and -211-3p with the chronic stage of the disease starting in adulthood. The analysis of putative targets linked the majority of dysregulated miRNAs with pathways involved in epilepsy. Our profiling uncovered miRNA expression characteristic for infantile and adulthood-onset epileptogenesis, suggesting the distinct biology underlying TLE in the onset age-dependent matter. Our results indicate the necessity of addressing the onset age as an important parameter in future epilepsy research.
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Affiliation(s)
- Petra Bencurova
- grid.10267.320000 0001 2194 0956CEITEC - Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic ,grid.412752.70000 0004 0608 7557Brno Epilepsy Center, Department of Neurology, St. Anne’s University Hospital and Medical Faculty of Masaryk University, Pekarska 53, 656 91 Brno, Czech Republic
| | - Jiri Baloun
- grid.10267.320000 0001 2194 0956CEITEC - Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
| | - Jakub Hynst
- grid.10267.320000 0001 2194 0956CEITEC - Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
| | - Jan Oppelt
- grid.10267.320000 0001 2194 0956CEITEC - Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic ,grid.25879.310000 0004 1936 8972Department of Pathology and Laboratory Medicine, Division of Neuropathology, Perelman School of Medicine, University of Pennsylvania, 19104-6100 Philadelphia, PA USA
| | - Hana Kubova
- grid.418095.10000 0001 1015 3316Department of Developmental Epileptology, Institute of Physiology, Academy of Sciences Czech Republic, Videnska 1083, 14220 Prague, Czech Republic
| | - Sarka Pospisilova
- grid.10267.320000 0001 2194 0956CEITEC - Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
| | - Milan Brazdil
- grid.10267.320000 0001 2194 0956CEITEC - Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic ,grid.412752.70000 0004 0608 7557Brno Epilepsy Center, Department of Neurology, St. Anne’s University Hospital and Medical Faculty of Masaryk University, Pekarska 53, 656 91 Brno, Czech Republic
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