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Chakraborty S, Rao S, Tripathi SJ. The neuroprotective effects of N-acetylcysteine in psychiatric and neurodegenerative disorders: From modulation of glutamatergic transmission to restoration of synaptic plasticity. Neuropharmacology 2025:110527. [PMID: 40414419 DOI: 10.1016/j.neuropharm.2025.110527] [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: 03/01/2025] [Revised: 05/10/2025] [Accepted: 05/21/2025] [Indexed: 05/27/2025]
Abstract
N-acetylcysteine (NAC) is an effective pleiotropic drug with a strong safety profile. It is predominantly used as a mucolytic agent and in the treatment of paracetamol overdose. However, extensive research in the last decade has shown the prominent efficacy of NAC in many neuropsychiatric and neurodegenerative disorders. NAC acts through multiple mechanisms; primarily, it releases cysteine and modulates glutamatergic and monoaminergic transmission. Further, it restores glutathione levels, promotes oxidative balance, reverses decreased synaptic plasticity, reduces neuroinflammation and mitochondrial dysfunction, and provides neurotrophic support. Additionally, it regulates one-carbon metabolism pathways, leading to the production of key metabolites. In this review, we will be discussing in-depth mechanisms of action of NAC and its promising ability to reverse neuropathological changes, particularly cognitive deficits, and associated plasticity changes in various psychiatric and neurodegenerative diseases, including depression, bipolar disorders, schizophrenia, Alzheimer's disease, Huntington's disease, traumatic brain injury, aging. Overall, several preclinical studies and clinical trials have demonstrated the efficacy of NAC in reversing regressive plasticity, cognitive deficits, and associated changes in the brain. NAC remains among the strongest candidates with a high safety profile for managing several types of neurological disorders.
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Affiliation(s)
- Suwarna Chakraborty
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Shankaranarayana Rao
- Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India.
| | - Sunil Jamuna Tripathi
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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Hinojosa-Figueroa MS, Cruz-Caraguay M, Torres Pasquel A, Puga Rosero V, Eguiguren Chavez CB, Rodas JA, Leon-Rojas JE. Etiologies of Multidrug-Resistant Epilepsy in Latin America: A Comprehensive Review of Structural, Genetic, Metabolic, Inflammatory, and Infectious Origins: A Systematic Review. Biomolecules 2025; 15:576. [PMID: 40305305 PMCID: PMC12025188 DOI: 10.3390/biom15040576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2025] [Revised: 04/06/2025] [Accepted: 04/12/2025] [Indexed: 05/02/2025] Open
Abstract
Epilepsy is a prevalent neurological disorder that affects millions worldwide, with a significant portion of individuals experiencing drug-resistant forms of the condition. In Latin America, the challenge of identifying the underlying causes of multidrug-resistant epilepsy (MDRE) is particularly pressing. (1) Background: This systematic review aims to highlight the critical importance of understanding the etiology of MDRE in Latin America. (2) Methods: A systematic review of Medline (PubMed), Scopus, and Web of Science was conducted following the PRISMA methodology; articles were selected if they included information on the etiology of MDRE in Latin-American participants, and the NHLBI tool was used to assess bias. (3) Results: A total of 37 published articles were finally included in the review. The most frequently documented cause of drug-resistant epilepsy was structural, affecting 725 patients, with hippocampal atrophy and sclerosis predominantly involving both the right and left lobes. The second most common cause was genetic, identified in 362 individuals who exhibited polymorphisms in genes such as ABCB1, CYP2C9, SCN1A, SLC6A4, and MDR-1, among others. The third most frequent cause was metabolic, and the fourth was inflammatory, affecting 258 individuals, which was associated with various inflammatory markers, including IL-1β, IL-6, CD8+, CD-25, and HLA-DR. Finally, infectious causes were also reported. (4) Conclusions: Structural causes are the leading etiology of MDRE in Latin America, followed by genetic, metabolic, inflammatory, and infectious origins. The regional pattern contrasts with findings from Europe and Asia, highlighting the influence of socioeconomic, environmental, and population-specific genetic factors. Our findings underscore the urgent need for regionally tailored research and interventions, particularly in understudied areas such as infectious causes and neuroinflammation.
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Affiliation(s)
- Mario S. Hinojosa-Figueroa
- NeurALL Research Group, Quito 170157, Ecuador; (M.S.H.-F.); (M.C.-C.); (A.T.P.); (V.P.R.); (C.B.E.C.)
- Escuela de Medicina, Universidad Internacional del Ecuador, Quito 170411, Ecuador
| | - Mishell Cruz-Caraguay
- NeurALL Research Group, Quito 170157, Ecuador; (M.S.H.-F.); (M.C.-C.); (A.T.P.); (V.P.R.); (C.B.E.C.)
- Facultad de Ciencias de la Salud, Universidad Técnica Particular de Loja, Loja 1101608, Ecuador
| | - Alejandro Torres Pasquel
- NeurALL Research Group, Quito 170157, Ecuador; (M.S.H.-F.); (M.C.-C.); (A.T.P.); (V.P.R.); (C.B.E.C.)
- Escuela de Medicina, Universidad Internacional del Ecuador, Quito 170411, Ecuador
| | - Vanesa Puga Rosero
- NeurALL Research Group, Quito 170157, Ecuador; (M.S.H.-F.); (M.C.-C.); (A.T.P.); (V.P.R.); (C.B.E.C.)
- Escuela de Medicina, Universidad Internacional del Ecuador, Quito 170411, Ecuador
| | | | - Jose A. Rodas
- School of Psychology, University College Dublin, D04 C1P1 Dublin, Ireland
- Escuela de Psicología, Universidad Espíritu Santo, Samborondón 092301, Ecuador
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Kumar A, Kumari S, Dhiman P, Singh D. Medium-Chain Triglycerides Supplementation Protects Epilepsy-Associated Behavioral Impairments in a Mouse Model. J Biochem Mol Toxicol 2025; 39:e70213. [PMID: 40114545 DOI: 10.1002/jbt.70213] [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: 02/22/2024] [Revised: 02/01/2025] [Accepted: 03/02/2025] [Indexed: 03/22/2025]
Abstract
Presently there has been a growing interest in the development of dietary-based interventions as alternative therapies to combat chronic neurological conditions like epilepsy. Medium-chain triglycerides (MCT) are composed of three fatty acids attached to a glycerol backbone and have shown several beneficial effects in various neurological diseases. The present study investigated MCT supplementation's impact on seizure severity and associated neurobehavioral comorbidities in a pentylenetetrazole (PTZ) mouse kindling model. Mice were administered 35 mg/kg (i.p.) of PTZ every other day for kindling induction. The kindled mice were then subjected to MCT supplementation for over 25 days with seizure scoring at every 5th day following PTZ exposure. Behavioral analysis was initiated at the end of 25 days of the MCT supplementation. After that, lipid peroxidation assay, and, gene and protein expression studies were performed in the isolated hippocampus. MCT significantly decreased seizure severity scores compared to control. The treatment reduced immobility duration in the forced swim and tail suspension tests, indicating a reversal of seizures-associated depression-like behavior. A significant reduction in the percentage of spontaneous alternation was observed in the kindled control group in the T-maze test, which remained unchanged following MCT supplementation in the treated group. Furthermore, no change was observed in the locomotion and anxiety index of the kindled mice supplemented with MCT compared to the control group. In addition, the supplementation attenuated the altered hippocampal lipid peroxidation, and mRNA and protein levels of mTOR and Gsk-3β. The study concluded that MCT supplementation suppresses epileptic seizures and associated depression-like behavior in kindled mice via interacting mTOR and Gsk-3β signaling.
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Affiliation(s)
- Amit Kumar
- Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Savita Kumari
- Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Poonam Dhiman
- Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Damanpreet Singh
- Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
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Xie W, Koppula S, Kale MB, Ali LS, Wankhede NL, Umare MD, Upaganlawar AB, Abdeen A, Ebrahim EE, El-Sherbiny M, Behl T, Shen B, Singla RK. Unraveling the nexus of age, epilepsy, and mitochondria: exploring the dynamics of cellular energy and excitability. Front Pharmacol 2024; 15:1469053. [PMID: 39309002 PMCID: PMC11413492 DOI: 10.3389/fphar.2024.1469053] [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: 07/23/2024] [Accepted: 08/20/2024] [Indexed: 09/25/2024] Open
Abstract
Epilepsy, a complex neurological condition marked by recurring seizures, is increasingly recognized for its intricate relationship with mitochondria, the cellular powerhouses responsible for energy production and calcium regulation. This review offers an in-depth examination of the interplay between epilepsy, mitochondrial function, and aging. Many factors might account for the correlation between epilepsy and aging. Mitochondria, integral to cellular energy dynamics and neuronal excitability, perform a critical role in the pathophysiology of epilepsy. The mechanisms linking epilepsy and mitochondria are multifaceted, involving mitochondrial dysfunction, reactive oxygen species (ROS), and mitochondrial dynamics. Mitochondrial dysfunction can trigger seizures by compromising ATP production, increasing glutamate release, and altering ion channel function. ROS, natural byproducts of mitochondrial respiration, contribute to oxidative stress and neuroinflammation, critical factors in epileptogenesis. Mitochondrial dynamics govern fusion and fission processes, influence seizure threshold and calcium buffering, and impact seizure propagation. Energy demands during seizures highlight the critical role of mitochondrial ATP generation in maintaining neuronal membrane potential. Mitochondrial calcium handling dynamically modulates neuronal excitability, affecting synaptic transmission and action potential generation. Dysregulated mitochondrial calcium handling is a hallmark of epilepsy, contributing to excitotoxicity. Epigenetic modifications in epilepsy influence mitochondrial function through histone modifications, DNA methylation, and non-coding RNA expression. Potential therapeutic avenues targeting mitochondria in epilepsy include mitochondria-targeted antioxidants, ketogenic diets, and metabolic therapies. The review concludes by outlining future directions in epilepsy research, emphasizing integrative approaches, advancements in mitochondrial research, and ethical considerations. Mitochondria emerge as central players in the complex narrative of epilepsy, offering profound insights and therapeutic potential for this challenging neurological disorder.
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Affiliation(s)
- Wen Xie
- Department of Pharmacy and Institutes for Systems Genetics, Center for High Altitude Medicine, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Sushruta Koppula
- College of Biomedical and Health Sciences, Konkuk University, Chungju-Si, Republic of Korea
| | - Mayur B. Kale
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, India
| | - Lashin S. Ali
- Department of Basic Medical Sciences, Faculty of Dentistry, Al-Ahliyya Amman University, Amman, Jordan
| | | | - Mohit D. Umare
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, India
| | | | - Ahmed Abdeen
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Benha University, Toukh, Egypt
| | - Elturabi E. Ebrahim
- Medical-Surgical Nursing Department, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Mohamed El-Sherbiny
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia
- Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Tapan Behl
- Amity School of Pharmaceutical Sciences, Amity University, Mohali, India
| | - Bairong Shen
- Institutes for Systems Genetics, West China Tianfu Hospital, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Rajeev K. Singla
- Department of Pharmacy and Institutes for Systems Genetics, Center for High Altitude Medicine, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
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Akdağ G, Canbaz Kabay S, Bican Demir A, Ergin Bakar E, Koç G, Üstün Özek S, Küçük A, Ünsal MA, Neyal A, Florentina Ateş M, Çelik HT, Kılıçparlar Cengiz E, Kutlu G, Ağırcan D, Karacan Gölen M, Bek S, Çınar N, Sahin S, Şişman Bayar AB, Terzi M, Kendirli Aslan S, Kenar SG, Kutluhan S, Ekmekyapar Fırat Y, Yılmaz Okuyan D, Bayar MD, Mert Atmaca M, Yalçın D, Genç F, Köse Leba L, Yılmaz B, Eren F, Bolu NE, Keskin Güler S, Akıncı T, Reyhani A, Yıldırım Sitembölükbaşı N, Türkmen N, Karşıdağ S, Velioğlu SK, Demir A, Haytı B, Hasırcı Bayır BR, Ezgi Uçan Tokuç F, Demir G, Çakmakçı G, Özkan H, Bulut O, Kesim Şahin Ö, Sürmeli R, Tekin S, Sarıoğlu ŞG, Gesoğlu Demir T, Akkoyun Arıkan F, Çetiner M. The effect of sleep disorders on quality of life in patients with epilepsy: A multicenter study from Turkey. Epilepsy Behav 2024; 150:109568. [PMID: 38141572 DOI: 10.1016/j.yebeh.2023.109568] [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: 06/23/2023] [Revised: 10/31/2023] [Accepted: 11/26/2023] [Indexed: 12/25/2023]
Abstract
OBJECTIVE We aimed to investigate sleep disorders in patients with epilepsy (PWE) and to investigate the effects of sleep disorders on quality of life. METHODS In our multicenter study conducted in Turkey, 1358 PWE were evaluated. The demographic and clinical data of the patients were recorded. The Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory (BDI), and Quality of Life in Epilepsy Inventory-10 (QOLIE-10) were administered. RESULTS The mean age of 1358 patients was 35.92 ± 14.11 (range, 18-89) years. Seven hundred fifty-one (55.30 %) were women. Some 12.7 % of the patients had insomnia (ISI > 14), 9.6 % had excessive daytime sleepiness (ESS > 10), 46.5 % had poor sleep quality (PSQI > 5), and 354 patients (26.1 %) had depressive symptoms (BDI > 16). The mean QOLIE-10 score was 22.82 ± 8.14 (10-48). Resistant epilepsy was evaluated as the parameter with the highest risk affecting quality of life Adjusted odds ratio (AOR = 3.714; 95 % confidence interval (CI): [2.440-5.652] < 0.001)). ISI (AOR = 1.184; 95 % CI: [1.128-1.243]; p < 0.001), ESS (AOR = 1.081; 95 % CI: [1.034-1.130]; p < 0.001), PSQI (AOR = 0.928; 95 % CI: [0.867 - 0.994]; p = 0.034), BDI (AOR = 1.106; 95 % CI: [1.084-1.129]; p < 0.001), epilepsy duration (AOR = 1.023; 95 % CI: [1.004-1.041]; p = 0.014), were determined as factors affecting quality of life. SIGNIFICANCE Sleep disorders are common in PWE and impair their quality of life. Quality of life can be improved by controlling the factors that may cause sleep disorders such as good seizure control, avoiding polypharmacy, and correcting the underlying mood disorders in patients with epilepsy.
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Affiliation(s)
- Gönül Akdağ
- Kutahya Health Sciences University, Faculty of Medicine, Department of Neurology, Kutahya, Türkiye.
| | - Sibel Canbaz Kabay
- Kutahya Health Sciences University, Faculty of Medicine, Department of Neurology, Kutahya, Türkiye.
| | - Aylin Bican Demir
- Uludağ University, Faculty of Medicine, Department of Neurology, Bursa, Türkiye.
| | - Ebru Ergin Bakar
- University of Health Sciences, Ankara Training and Research Hospital, Department of Neurology, Ankara, Türkiye.
| | - Güray Koç
- University of Health Sciences, Ankara City Hospital, Department of Neurology, Ankara, Türkiye
| | - Sibel Üstün Özek
- University of Health Sciences, Prof.Dr.Cemil Taşçıoğlu City Hospital, Department of Neurology, İstanbul, Türkiye.
| | - Ahmet Küçük
- University of Health Sciences, Konya Beyhekim Training and Research Hospital, Neurology Clinic, Konya, Türkiye.
| | - Miraç Ayşen Ünsal
- Sultan 2.Abdulhamid Khan Educational and Research Hospital, Department of Neurology, Istanbul, Türkiye.
| | - Abdurrahman Neyal
- Gaziantep Islam Science and Technology University School of Medicine, Department of Neurology, Gaziantep, Türkiye.
| | | | - Havva Tuğba Çelik
- Haydarpasa Numune Training and Research Hospital, İstanbul, Türkiye.
| | | | - Gülnihal Kutlu
- Muğla Sıtkı Koçman University, Faculty of Medicine, Department of Neurology, Muğla, Türkiye.
| | - Dilek Ağırcan
- Harran University, Faculty of Medicine, Department of Neurology, Sanlıurfa, Türkiye.
| | | | - Semai Bek
- Muğla Sıtkı Koçman University, Faculty of Medicine, Department of Neurology, Muğla, Türkiye.
| | - Nilgün Çınar
- Maltepe University, Faculty of Medicine, Department of Neurology, Istanbul, Türkiye.
| | - Sevki Sahin
- University of Health Sciences, Hamidiye Faculty of Medicine, Department of Neurology, Sancaktepe Sehit Prof. Dr. Ilhan Varank SUAM, Istanbul, Türkiye.
| | - Aysel Büşra Şişman Bayar
- Haseki Training and Research Hospital, University of Health Sciences, Department of Neurology, Istanbul, Türkiye.
| | - Murat Terzi
- Ondokuz Mayıs University, Faculty of Medicine, Department of Neurology, Samsun, Türkiye.
| | - Sude Kendirli Aslan
- Maltepe University, Faculty of Medicine, Department of Neurology, Istanbul, Türkiye.
| | - Safiye Gül Kenar
- Necmettin Erbakan University, Faculty of Medicine, Department of Neurology, Konya, Türkiye.
| | - Süleyman Kutluhan
- Süleyman Demirel University, Faculty of Medicine, Department of Neurology, Isparta, Türkiye.
| | | | | | - Muhammet Duran Bayar
- Gaziosmanpaşa Training and Research Hospital, University of Health Sciences, Department of Neurology, Istanbul, Türkiye.
| | - Murat Mert Atmaca
- Sultan 2.Abdulhamid Khan Educational and Research Hospital, Department of Neurology, Istanbul, Türkiye.
| | - Destina Yalçın
- Maltepe University, Faculty of Medicine, Department of Neurology, Istanbul, Türkiye.
| | - Fatma Genç
- University of Health Sciences Antalya Training and Research Hospital, Department of Neurology, Antalya, Türkiye.
| | - Leyla Köse Leba
- Necmettin Erbakan University, Faculty of Medicine, Department of Neurology, Konya, Türkiye.
| | - Buket Yılmaz
- SANKO University School of Medicine, Department of Neurology, Gaziantep, Türkiye.
| | - Fettah Eren
- Selçuk University, Faculty of Medicine, Department of Neurology, Konya, Türkiye.
| | - Naci Emre Bolu
- Maltepe University, Faculty of Medicine, Department of Neurology, Istanbul, Türkiye.
| | - Selda Keskin Güler
- University of Health Sciences, Ankara Training and Research Hospital, Department of Neurology, Ankara, Türkiye.
| | - Tuba Akıncı
- Haydarpasa Numune Training and Research Hospital, İstanbul, Türkiye.
| | - Aylin Reyhani
- Sultan 2.Abdulhamid Khan Educational and Research Hospital, Department of Neurology, Istanbul, Türkiye.
| | | | - Nur Türkmen
- Tekirdağ Dr İsmail Fehmi Cumalıoğlu City Hospital, Clinic of Clinical Neurophysiology, Tekirdağ, Türkiye.
| | - Sibel Karşıdağ
- Sultan 2.Abdulhamid Khan Educational and Research Hospital, Department of Neurology, Istanbul, Türkiye.
| | - Sibel K Velioğlu
- Karadeniz Technical University, Faculty of Medicine, Department of Neurology, Clinical Neurophysiology Unit, Trabzon, Türkiye.
| | | | - Barış Haytı
- Pamukkale University, School of Medicine, Department of Neurology, Denizli, Turkey.
| | | | - Firdevs Ezgi Uçan Tokuç
- University of Health Sciences Antalya Training and Research Hospital, Department of Neurology, Antalya, Türkiye
| | - Göksemin Demir
- Pamukkale University, School of Medicine, Department of Neurology, Denizli, Turkey.
| | - Güngör Çakmakçı
- Kutahya Health Sciences University, Faculty of Medicine, Department of Neurology, Kutahya, Türkiye.
| | - Hülya Özkan
- Trakya University, School of Medicine, Department of Neurology, Edirne, Türkiye.
| | | | - Özlem Kesim Şahin
- Haydarpasa Numune Training and Research Hospital, İstanbul, Türkiye.
| | - Reyhan Sürmeli
- Ümraniye Training and Research Hospital, Istanbul, Türkiye.
| | - Selma Tekin
- Pamukkale University, School of Medicine, Department of Neurology, Denizli, Turkey.
| | - Şerife Gizem Sarıoğlu
- Süleyman Demirel University, Faculty of Medicine, Department of Neurology, Isparta, Türkiye.
| | - Tülin Gesoğlu Demir
- Harran University, Faculty of Medicine, Department of Neurology, Sanlıurfa, Türkiye.
| | - Fatma Akkoyun Arıkan
- Kutahya Health Sciences University, Faculty of Medicine, Department of Neurology, Kutahya, Türkiye.
| | - Mustafa Çetiner
- Kutahya Health Sciences University, Faculty of Medicine, Department of Neurology, Kutahya, Türkiye.
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Madireddy S, Madireddy S. Therapeutic Strategies to Ameliorate Neuronal Damage in Epilepsy by Regulating Oxidative Stress, Mitochondrial Dysfunction, and Neuroinflammation. Brain Sci 2023; 13:brainsci13050784. [PMID: 37239256 DOI: 10.3390/brainsci13050784] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/09/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
Epilepsy is a central nervous system disorder involving spontaneous and recurring seizures that affects 50 million individuals globally. Because approximately one-third of patients with epilepsy do not respond to drug therapy, the development of new therapeutic strategies against epilepsy could be beneficial. Oxidative stress and mitochondrial dysfunction are frequently observed in epilepsy. Additionally, neuroinflammation is increasingly understood to contribute to the pathogenesis of epilepsy. Mitochondrial dysfunction is also recognized for its contributions to neuronal excitability and apoptosis, which can lead to neuronal loss in epilepsy. This review focuses on the roles of oxidative damage, mitochondrial dysfunction, NAPDH oxidase, the blood-brain barrier, excitotoxicity, and neuroinflammation in the development of epilepsy. We also review the therapies used to treat epilepsy and prevent seizures, including anti-seizure medications, anti-epileptic drugs, anti-inflammatory therapies, and antioxidant therapies. In addition, we review the use of neuromodulation and surgery in the treatment of epilepsy. Finally, we present the role of dietary and nutritional strategies in the management of epilepsy, including the ketogenic diet and the intake of vitamins, polyphenols, and flavonoids. By reviewing available interventions and research on the pathophysiology of epilepsy, this review points to areas of further development for therapies that can manage epilepsy.
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Affiliation(s)
- Sahithi Madireddy
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Maes MHJ, Stoyanov D. False dogmas in mood disorders research: Towards a nomothetic network approach. World J Psychiatry 2022; 12:651-667. [PMID: 35663296 PMCID: PMC9150032 DOI: 10.5498/wjp.v12.i5.651] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 10/07/2021] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
The current understanding of major depressive disorder (MDD) and bipolar disorder (BD) is plagued by a cacophony of controversies as evidenced by competing schools to understand MDD/BD. The DSM/ICD taxonomies have cemented their status as the gold standard for diagnosing MDD/BD. The aim of this review is to discuss the false dogmas that reign in current MDD/BD research with respect to the new, data-driven, machine learning method to model psychiatric illness, namely nomothetic network psychiatry (NNP). This review discusses many false dogmas including: MDD/BD are mind-brain disorders that are best conceptualized using a bio-psycho-social model or mind-brain interactions; mood disorders due to medical disease are attributable to psychosocial stress or chemical imbalances; DSM/ICD are the gold standards to make the MDD/BD diagnosis; severity of illness should be measured using rating scales; clinical remission should be defined using threshold values on rating scale scores; existing diagnostic BD boundaries are too restrictive; and mood disorder spectra are the rule. In contrast, our NNP models show that MDD/BD are not mind-brain or psycho-social but systemic medical disorders; the DSM/ICD taxonomies are counterproductive; a shared core, namely the reoccurrence of illness (ROI), underpins the intertwined recurrence of depressive and manic episodes and suicidal behaviors; mood disorders should be ROI-defined; ROI mediates the effects of nitro-oxidative stress pathways and early lifetime trauma on the phenome of mood disorders; severity of illness and treatment response should be delineated using the NNP-derived causome, pathway, ROI and integrated phenome scores; and MDD and BD are the same illness.
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Affiliation(s)
- Michael HJ Maes
- Department of Psychiatry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Drozdstoy Stoyanov
- Department of Psychiatry, Medical University Plovdiv, Plovdiv 4000, Bulgaria
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A Novel Pathway Phenotype of Temporal Lobe Epilepsy and Comorbid Psychiatric Disorders: Results of Precision Nomothetic Medicine. Antioxidants (Basel) 2022; 11:antiox11050803. [PMID: 35624666 PMCID: PMC9137678 DOI: 10.3390/antiox11050803] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/13/2022] [Accepted: 04/13/2022] [Indexed: 02/01/2023] Open
Abstract
No precision medicine models of temporal lobe epilepsy (TLE) and associated mental comorbidities have been developed to date. This observational study aimed to develop a precision nomothetic, data-driven comorbid TLE model with endophenotype classes and pathway phenotypes that may have prognostic and therapeutical implications. We recruited forty healthy controls and 108 TLE patients for this research and assessed TLE and psychopathology (PP) features as well as oxidative stress (OSTOX, e.g., malondialdehyde or MDA, lipid hydroperoxides, and advanced oxidation protein products) and antioxidant (paraoxonase 1 or PON1 status, -SH groups, and total radical trapping potential or TRAP) biomarkers. A large part (57.2%) of the variance in a latent vector (LV) extracted from the above TLE and PP features was explained by these OSTOX and antioxidant biomarkers. The PON1 Q192R genetic variant showed indirect effects on this LV, which were completely mediated by PON1 activity and MDA. Factor analysis showed that a common core could be extracted from TLE, PP, OSTOX and antioxidant scores, indicating that these features are manifestations of a common underlying construct, i.e., a novel pathway phenotype of TLE. Based on the latter, we constructed a new phenotype class that is characterized by increased severity of TLE, PP and OSTOX features and lowered antioxidant defenses. A large part of the variance in episode frequency was explained by increased MDA, lowered antioxidant, and nitric oxide metabolite levels. In conclusion, (a) PP symptoms belong to the TLE phenome, and the signal increased severity; and (b) cumulative effects of aldehyde formation and lowered antioxidants determine epileptogenic kindling.
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Perceived quality of life (QOLIE-31-P), depression (NDDI-E), anxiety (GAD-7), and insomnia in patients with epilepsy attended at a refractory epilepsy unit in real-life clinical practice. Neurol Sci 2021; 43:1955-1964. [PMID: 34524559 PMCID: PMC8440152 DOI: 10.1007/s10072-021-05595-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 09/06/2021] [Indexed: 11/26/2022]
Abstract
Objectives This study aims to evaluate the relationship between psychiatric comorbidity (anxiety and depression), somnolence, and quality of life, using validated scales in patients with epilepsy in real-life clinical practice and clinical and demographic variables. Methods A cross-sectional observational study was conducted. Self-administered scales of anxiety disorders (GAD-7), depression (NDDI-E), somnolence (Epworth Sleepiness Scale (ESS)), and quality of life (QOLIE-31-P) in patients with epilepsy treated in the refractory epilepsy unit of a tertiary hospital were employed. Results Eighty-four patients, 44.3 ± 17.4 years, 48.2% women, epilepsy duration 21.5 ± 15.9 years, and number of antiepileptic drugs 1.9 ± 1.2 were included. Severe anxiety was present in 14.3%, depression in 20.2%, and somnolence in 14.3% of patients. QOLIE-31-P score was 62.0 ± 19.2. Depression and focal epilepsy (OR = 4.5[1.3, 20.7], p = 0.029), as well as anxiety and temporal lobe epilepsy (OR = 4.3 [1.0, 18.1], p = 0.044), were associated. Moreover, relationships between worse quality of life and higher scores from NDDI-E (β = − 1.42, adjusted p = 0.006) and GAD-7 (β = − 1.21, adjusted p = 0.006), especially in drug-resistant epilepsy (β = − 8.08, adjusted p = 0.045) and female sex (β = − 7.83, adjusted p = 0.034), were identified. Statistically significant negative associations were observed between problems to fall asleep and overall quality of life score (β = − 11.64, adjusted p = 0.022), sleep disturbance and energy (β = − 14.78, adjusted p = 0.027), and mood (β = 12.40, adjusted p = 0.027) scores. Conclusions The multidimensional evaluation revealed that higher levels of anxiety and depression are associated with worse quality of life in real clinical practice in patients with epilepsy, especially in females and drug-resistant epilepsy. In addition, sleep disturbances are associated with particular aspects of the quality of life. Further studies with longitudinal follow-up would be useful to adequately manage these comorbidities in patients with epilepsy. Supplementary Information The online version contains supplementary material available at 10.1007/s10072-021-05595-3.
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Maes M, Supasitthumrong T, Limotai C, Michelin AP, Matsumoto AK, de Oliveira Semão L, de Lima Pedrão JV, Moreira EG, Carvalho AF, Sirivichayakul S, Barbosa DS, Kanchanatawan B. Increased Oxidative Stress Toxicity and Lowered Antioxidant Defenses in Temporal Lobe Epilepsy and Mesial Temporal Sclerosis: Associations with Psychiatric Comorbidities. Mol Neurobiol 2020; 57:3334-3348. [PMID: 32514863 DOI: 10.1007/s12035-020-01949-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 05/22/2020] [Indexed: 01/26/2023]
Abstract
Oxidative stress toxicity (OSTOX), as well as lowered antioxidant defenses (ANTIOX), plays a role in temporal lobe epilepsy (TLE). Nevertheless, the associations between OSTOX/ANTIOX and psychiatric comorbidities in TLE are largely unknown. Thus, this study examines plasma malondialdehyde (MDA), lipid hydroperoxides (LOOH), advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), total radical-trapping antioxidant parameter (TRAP), and sulfhydryl (-SH) groups in depression due to TLE (n = 25); anxiety disorders due to TLE (n = 27); psychotic disorder due to TLE (n = 25); "pure TLE" (n = 27); and healthy controls (n = 40). TLE and mesial temporal sclerosis (MTS) were characterized by significant increases in OSTOX (MDA, AOPP, LOOH) and lowered ANTIOX (-SH groups, TRAP). The discrimination of pure TLE from controls yielded a significant area under the ROC curve for MDA (0.999), AOPP (0.851), -SH groups (0.899), and the OSTOX/ANTIOX ratio (0.996). Seizure frequency is significantly associated with increased MDA and lowered LOOH and NOx levels. Increased MDA was associated with the severity of depressive and physiosomatic symptoms, while increased AOPP levels predicted suicidal ideation. Depression and anxiety disorders co-occurring with TLE showed significantly lower MDA levels than TLE without any comorbidities. The psychotic and negative symptoms of TLE are associated with increased MDA levels and excitation with increased LOOH and lowered TRAP levels. These results indicate that oxidative stress toxicity especially protein oxidation and aldehyde formation coupled with lowered -SH groups plays a key role in the pathophysiology of TLE/MTS. Increased aldehyde formation also impacts psychopathology and psychosis, as well as negative and depressive symptoms.
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Affiliation(s)
- Michael Maes
- Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria.,IMPACT Strategic Research Center, Deakin University, Geelong, Australia
| | - Thitiporn Supasitthumrong
- Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Chusak Limotai
- Chulalongkorn Comprehensive Epilepsy Center of Excellence (CCEC), The Thai Red Cross Society; Division of Neurology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Ana Paula Michelin
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, PR, Brazil
| | - Andressa Keiko Matsumoto
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, PR, Brazil
| | - Laura de Oliveira Semão
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, PR, Brazil
| | - João Victor de Lima Pedrão
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, PR, Brazil
| | | | - Andre F Carvalho
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada.,Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
| | | | - Décio Sabbatini Barbosa
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, PR, Brazil
| | - Buranee Kanchanatawan
- Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
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Protective Effects of Artemisia persica Essential Oil Against Pentylenetetrazol-Induced Seizure in Male Mice with Emphasizing its Mechanism of Action. IRANIAN RED CRESCENT MEDICAL JOURNAL 2019. [DOI: 10.5812/ircmj.85021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Depression and quality of life in patients with epilepsy in Northwest Greece. Seizure 2019; 66:93-98. [PMID: 30818183 DOI: 10.1016/j.seizure.2019.02.012] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 02/12/2019] [Accepted: 02/19/2019] [Indexed: 12/18/2022] Open
Abstract
PURPOSE The purpose of the present study was to compare depression and QoL between patients with epilepsy and healthy controls, evaluating potentially related factors to depression and QoL in patients with epilepsy in Northwest Greece. METHODS A case study was conducted in adult patients with epilepsy followed up at the University Hospital of Ioannina and in healthy controls. The Patient Health Questionnaire (PHQ-9) for depression's severity evaluation, the WHOQOL-BREF questionnaire for the QoL estimation and the Adverse Event Profile (AEP) questionnaire for the Antiepileptic Drugs (AEDs) adverse effects assessment were used. RESULTS Seventy patients with epilepsy and 70 controls were recruited. The PHQ-9 score was higher in patients compared to controls and slightly higher than reported in patients with epilepsy. PHQ-9 was significantly associated with the AEP score. Our patients had a poorer QoL compared to controls. The level of education, the AEP and the PHQ-9 scores were associated to QoL, the last two being the most powerful predictors of QoL. CONCLUSION Patients with epilepsy in Northwest Greece had higher rates of depression than reported in patients with epilepsy and poorer QoL compared to controls. The adverse effects of AEDs were related to depression in our study, while the adverse effects of AEDs and depression were more powerful predictors of QoL compared to demographics and other characteristics of epilepsy.
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The Effect of Metformin in Experimentally Induced Animal Models of Epileptic Seizure. Behav Neurol 2019; 2019:6234758. [PMID: 30863464 PMCID: PMC6378775 DOI: 10.1155/2019/6234758] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 12/08/2018] [Accepted: 12/17/2018] [Indexed: 12/27/2022] Open
Abstract
Background Epilepsy is one of the common neurological illnesses which affects millions of individuals globally. Although the majority of epileptic patients have a good response for the currently available antiepileptic drugs (AEDs), about 30-40% of epileptic patients are developing resistance. In addition to low safety profiles of most of existing AEDs, there is no AED available for curative or disease-modifying actions for epilepsy so far. Objectives This systematic review is intended to evaluate the effect of metformin in acute and chronic animal models of an epileptic seizure. Methods We searched PubMed, SCOPUS, Sciences Direct, and grey literature in order to explore articles published in English from January 2010 to November 2018, using key terms “epilepsy,” “seizure,” “metformin,” “oral hypoglycemic agents,” and “oral antidiabetic drugs”. The qualities of all the included articles were assessed according to the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES). Results Out of six hundred fifty original articles retrieved, eleven of them fulfilled the inclusion criteria and were included for final qualitative analysis. In these studies, metformin showed to control seizure attacks by attenuating seizure generation, delaying the onset of epilepsy, reducing hippocampal neuronal loss, and averting cognitive impairments in both acute and chronic models of an epileptic seizure. The possible mechanisms for its antiseizure or antiepileptic action might be due to activation of AMPK, antiapoptotic, antineuroinflammatory, and antioxidant properties, which possibly modify disease progression through affecting epileptogenesis. Conclusion This review revealed the benefits of metformin in alleviating symptoms of epileptic seizure and modifying different cellular and molecular changes that affect the natural history of the disease in addition to its good safety profile.
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