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Martella F, Caporali A, Macellaro M, Cafaro R, De Pasquale F, Dell'Osso B, D'Addario C. Biomarker identification in bipolar disorder. Pharmacol Ther 2025; 268:108823. [PMID: 39965667 DOI: 10.1016/j.pharmthera.2025.108823] [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: 06/04/2024] [Revised: 02/04/2025] [Accepted: 02/14/2025] [Indexed: 02/20/2025]
Abstract
Bipolar disorder (BD) is a severe psychiatric condition whose pathophysiology is complex and multifactorial. Genetic, environmental and social risk factors play a role in its development as well as in its progressive course. Research is currently focusing on the identification of the biological basis underlying these processes in order to suggest novel biomarkers capable to predict BD etiopathogenesis and staging. Staging has been recognized as of great value for the treatment and management of many illnesses and might also be suitable for mental health issues, particularly in disorders like BD, which progress from an initial mild phase to a more severe and thus difficult-to-treat situation. Thus, it would be of great help the characterization of to suggest better treatment requirements and improve prognosis across the different stages of the illness. Here, we summarize current research on the biological hypotheses of BD and the biomarkers associated with its progression, reviewing clinical studies available in the literature.
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Affiliation(s)
- Francesca Martella
- Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Andrea Caporali
- Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy; International School of Advanced Studies, University of Camerino, Camerino, Italy
| | - Monica Macellaro
- Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy; CRC "Aldo Ravelli" for Neurotechnology and Experimental Brain Therapeutics, University of Milan, Milan, Italy
| | - Rita Cafaro
- Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy
| | - Francesco De Pasquale
- Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy; IRCCS Fondazione Santa Lucia, Roma, Italy
| | - Bernardo Dell'Osso
- Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy; CRC "Aldo Ravelli" for Neurotechnology and Experimental Brain Therapeutics, University of Milan, Milan, Italy; Department of Psychiatry and Behavioural Sciences, Stanford University, Stanford, CA, USA
| | - Claudio D'Addario
- Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
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González-Martínez C, Haarkötter C, Carnero-Montoro E, Lorente JA, Lorente M. Epigenetic changes produced in women victims of intimate partner violence: A systematic review. WOMEN'S HEALTH (LONDON, ENGLAND) 2024; 20:17455057241290335. [PMID: 39568400 PMCID: PMC11580075 DOI: 10.1177/17455057241290335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/19/2024] [Accepted: 09/20/2024] [Indexed: 11/22/2024]
Abstract
BACKGROUND Intimate partner violence (IPV) is a prevalent form of violence against women that encompasses physical, sexual, and emotional abuse, as well as controlling behaviors by intimate partners, and predisposes the victims to multiple diseases. OBJECTIVE This systematic review aims to identify epigenetic marks associated with IPV and the resultant stress experienced by victims. DESIGN This study is a systematic review conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines. The review includes a comprehensive search and analysis of relevant literature to identify epigenetic changes associated with IPV. DATA SOURCES AND METHODS A systematic search was conducted across four databases: PubMed, Scopus, Web of Science, and ProQuest, using keywords related to IPV and epigenetics. The inclusion criteria were studies published in scientific journals with an experimental approach, focused on female survivors of gender-based violence, and providing information on epigenetic changes. The review included studies published up to June 15, 2024, with no time limits imposed, focusing on female victims of IPV. The inclusion criteria were studies published in scientific journals with an experimental approach, focused on female survivors of gender-based violence, and providing information on epigenetic changes. RESULTS The results revealed that epigenetic changes associated with IPV predominantly affect genes related to the glucocorticoid receptor, insulin-like growth factors, BDNF, and CPLX genes. These observations suggest that IPV is linked to significant epigenetic modifications in both victims and their offspring. CONCLUSION It is concluded that IPV is associated with epigenetic changes both in the woman and in her offspring. These findings underscore the importance of understanding the biological embedding of IPV through epigenetic research to better address the long-term health consequences for women. However, more studies are necessary to validate these results.
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Affiliation(s)
- Coral González-Martínez
- Centre for Genomics and Oncological Research, Pfizer-University of Granada, PTS Granada, Granada, Spain
- LABIGEN, Department of Legal Medicine, School of Medicine, PTS, University of Granada, UGR, Granada, Spain
| | - Christian Haarkötter
- LABIGEN, Department of Legal Medicine, School of Medicine, PTS, University of Granada, UGR, Granada, Spain
| | - Elena Carnero-Montoro
- Centre for Genomics and Oncological Research, Pfizer-University of Granada, PTS Granada, Granada, Spain
| | - Jose A Lorente
- Centre for Genomics and Oncological Research, Pfizer-University of Granada, PTS Granada, Granada, Spain
- LABIGEN, Department of Legal Medicine, School of Medicine, PTS, University of Granada, UGR, Granada, Spain
| | - Miguel Lorente
- LABIGEN, Department of Legal Medicine, School of Medicine, PTS, University of Granada, UGR, Granada, Spain
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Zakaria WNA, Wijaya A, Al-Rahbi B, Ahmad AH, Zakaria R, Othman Z. Emerging trends in gene and bipolar disorder research: a bibliometric analysis and network visualisation. Psychiatr Genet 2023; 33:102-112. [PMID: 36825833 DOI: 10.1097/ypg.0000000000000338] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
This study aims to use a bibliometric technique to evaluate the scientific output of gene and bipolar disorder research. The search query related to gene and bipolar disorder from the Scopus database identified 1848 documents from 1951 to 2020. The growth in the publications increased since early 1990, peaked in 2011, and started to decline thereafter. High occurrence in author keywords suggests that some research topics, such as "polymorphism", "linkage" and "association study" have waned over time, whereas others, such as "DNA methylation," "circadian rhythm," "" and "meta-analysis," are now the emerging trends in gene and bipolar disorder research. The USA was the country with the highest production followed by the UK, Canada, Italy and Germany. The leading institutions were Cardiff University in the UK, the National Institute of Mental Health (NIMH) in the USA, King's College London in the UK and the University of California, San Diego in the USA. The leading journals publishing gene and bipolar literature were the American Journal of Medical Genetics Neuropsychiatric Genetics, Molecular Psychiatry and Psychiatric Genetics. The top authors in the number of publications were Craddock N, Serretti A and Rietschel M. According to the co-authorship network analysis of authors, the majority of the authors in the same clusters were closely linked together and originated from the same or neighbouring country. The findings of this study may be useful in identifying emerging topics for future research and promoting research collaboration in the field of genetic studies related to bipolar disorder.
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Affiliation(s)
- Wan Nur Amalina Zakaria
- Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia Health Campus, Kubang Kerian, Kelantan, Malaysia
| | - Adi Wijaya
- Department of Health Information Management, Universitas Indonesia Maju, Jakarta, Indonesia
| | | | | | | | - Zahiruddin Othman
- Department of Psychiatry, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
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Shahyad S, Kheirabadi GR, Jahromi GP, Massaly M. Brain-derived Neurotrophic Factor and High Sensitive C-reactive Protein in Bipolar Depression and Unipolar Depression: The Practical Usage as a Discriminatory Tool. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE : THE OFFICIAL SCIENTIFIC JOURNAL OF THE KOREAN COLLEGE OF NEUROPSYCHOPHARMACOLOGY 2023; 21:108-117. [PMID: 36700317 PMCID: PMC9889908 DOI: 10.9758/cpn.2023.21.1.108] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/26/2021] [Accepted: 11/04/2021] [Indexed: 01/27/2023]
Abstract
Objective Brain-derived neurotrophic factor (BDNF) and high sensitive C-reactive protein (hs-CRP) have been reported to play roles in depression and bipolar disorder (BD). However, the probable discriminatory properties of these biologic markers are less investigated. We aimed to assess the serum BDNF and hs-CRP levels among Iranian patients with major depressive disorder (MDD) and BD during a depressive episode and investigate the optimum cut-off point for differential diagnosis of BD and MDD. Methods We recruited 30 patients with MDD, 30 with BD in depressive mood and 30 healthy comparators. Blood sample was taken from each participant to measure BDNF and hs-CRP levels. We also used receiver operating characteristic (ROC) curve analysis to find an optimal cut-off point for differentiating MDD from BD according to pre-defined variables. Results The mean age of total study population was 37.3 ± 5.0 years (males: 49%). BDNF was significantly lower in patients with BD, followed by MDD subjects and healthy controls 541.0 ± 601.0 pg/ml vs. 809.5 ± 433.3 pg/ml vs. 1,482.1 ± 519.8, respectively, p < 0.001). The area under curve of ROC curve analysis for BD versus MDD was 0.704 (95% confidence interval: 0.564-0.844, p = 0.007). We also found that the BDNF cut-off value of 504 could appropriately distinguished BD from MDD (sensitivity: 73%, specificity: 70%). No significant association were identified in terms of hs-CRP levels. Conclusion Patients suffering from BD had lowest BDNF levels compared to MDD or healthy adults and this biomarker could play a practical role differentiating MDD from BD. Several studies are required confirming our outcomes.
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Affiliation(s)
- Shima Shahyad
- Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran,Address for correspondence: Shima Shahyad Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Molla-sadra St, Tehran 1435916471, Iran, E-mail: , ORCID: https://orcid.org/0000-0002-5483-5367
| | - Gholam Reza Kheirabadi
- Behavioral Sciences Research Center, Department of Psychiatry, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Gila Pirzad Jahromi
- Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Muhammad Massaly
- Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Bonacina G, Carollo A, Esposito G. The Genetic Side of the Mood: A Scientometric Review of the Genetic Basis of Mood Disorders. Genes (Basel) 2023; 14:genes14020352. [PMID: 36833279 PMCID: PMC9956267 DOI: 10.3390/genes14020352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/22/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
Mood disorders are highly heritable psychiatric disorders. Over the years, many genetic polymorphisms have been identified to pose a higher risk for the development of mood disorders. To overview the literature on the genetics of mood disorders, a scientometric analysis was performed on a sample of 5342 documents downloaded from Scopus. The most active countries and the most impactful documents in the field were identified. Furthermore, a total of 13 main thematic clusters emerged in the literature. From the qualitative inspection of clusters, it emerged that the research interest moved from a monogenic to a polygenic risk framework. Researchers have moved from the study of single genes in the early 1990s to conducting genome-wide association studies around 2015. In this way, genetic overlaps between mood disorders and other psychiatric conditions emerged too. Furthermore, around the 2010s, the interaction between genes and environmental factors emerged as pivotal in understanding the risk for mood disorders. The inspection of thematic clusters provides a valuable insight into the past and recent trends of research in the genetics of mood disorders and sheds light onto future lines of research.
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Scotti-Muzzi E, Chile T, Vallada H, Otaduy MCG, Soeiro-de-Souza MG. BDNF rs6265 differentially influences neurometabolites in the anterior cingulate of healthy and bipolar disorder subjects. Brain Imaging Behav 2023; 17:282-293. [PMID: 36630045 DOI: 10.1007/s11682-023-00757-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 12/12/2022] [Accepted: 01/04/2023] [Indexed: 01/12/2023]
Abstract
Brain-derived neurotrophic factor (BDNF) is the most abundant brain neurotrophin and plays a critical role in neuronal growth, survival and plasticity, implicated in the pathophysiology of Bipolar Disorders (BD). The single-nucleotide polymorphism in the BDNF gene (BDNF rs6265) has been associated with decreased hippocampal BDNF secretion and volume in met carriers in different populations, although the val allele has been reported to be more frequent in BD patients. The anterior cingulate cortex (ACC) is a key center integrating cognitive and affective neuronal connections, where consistent alterations in brain metabolites such as Glx (Glutamate + Glutamine) and N-acetylaspartate (NAA) have been consistently reported in BD. However, little is known about the influence of BDNF rs6265 on neurochemical profile in the ACC of Healthy Controls (HC) and BD subjects. The aim of this study was to assess the influence of BDNF rs6265 on ACC neurometabolites (Glx, NAA and total creatine- Cr) in 124 euthymic BD type I patients and 76 HC, who were genotyped for BDNF rs6265 and underwent a 3-Tesla proton magnetic resonance imaging and spectroscopy scan (1 H-MRS) using a PRESS ACC single-voxel (8cm3) sequence. BDNF rs6265 polymorphism showed a significant two-way interaction (diagnosis × genotype) in relation to NAA/Cr and total Cr. While met carriers presented increased NAA/Cr in HC, BD-I subjects with the val allele revealed higher total Cr, denoting an enhanced ACC metabolism likely associated with increased glutamatergic metabolites observed in BD-I val carriers. However, these results were replicated only in men. Therefore, our results support evidences that the BDNF rs6265 polymorphism exerts a complex pleiotropic effect on ACC metabolites influenced by the diagnosis and sex.
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Affiliation(s)
- Estêvão Scotti-Muzzi
- Institute of Psychiatry, School of Medicine, University of São Paulo (IPq-FMUSP), São Paulo, Brazil.
| | - Thais Chile
- Genetics and Pharmacogenetics Unit (PROGENE), Institute of Psychiatry, School of Medicine, University of São Paulo (IPq-FMUSP), São Paulo, Brazil
| | - Homero Vallada
- Genetics and Pharmacogenetics Unit (PROGENE), Institute of Psychiatry, School of Medicine, University of São Paulo (IPq-FMUSP), São Paulo, Brazil
| | - Maria Concepción Garcia Otaduy
- Laboratory of Magnetic Resonance in Neuroradiology LIM44, Department and Institute of Radiology, School of Medicine, University of São Paulo (FMUSP), São Paulo, Brazil
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Pedigree-based study to identify GOLGB1 as a risk gene for bipolar disorder. Transl Psychiatry 2022; 12:390. [PMID: 36115840 PMCID: PMC9482626 DOI: 10.1038/s41398-022-02163-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 09/06/2022] [Accepted: 09/08/2022] [Indexed: 11/08/2022] Open
Abstract
Bipolar disorder (BD) is a complex psychiatric disorder with strong heritability. Identification of new BD risk genes will help determine the mechanism underlying disease pathogenesis. In the present study, we carried out whole genome sequencing for a Chinese BD family with three affected members and three unaffected members, and identified multiple candidate causal variations, including a frameshift mutation in the GOLGB1 gene. Since a GOLGB1 missense mutation was also found in another BD pedigree, we carried out functional studies by downregulating Golgb1 expression in the brain of neonatal mice. Golgb1 deficiency had no effect on anxiety, memory, and social behaviors in young adult mice. However, we found that young adult mice with Golgb1 deficiency exhibited elevated locomotor activity and decreased depressive behaviors in the tail suspension test and the sucrose preference test, but increased depressive behaviors in the forced swim test, resembling the dual character of BD patients with both mania and depression. Moreover, Golgb1 downregulation reduced PSD93 levels and Akt phosphorylation in the brain. Together, our results indicate that GOLGB1 is a strong BD risk gene candidate whose deficiency may result in BD phenotypes possibly through affecting PSD93 and PI3K/Akt signaling.
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Ochoa ELM. Lithium as a Neuroprotective Agent for Bipolar Disorder: An Overview. Cell Mol Neurobiol 2022; 42:85-97. [PMID: 34357564 PMCID: PMC11441275 DOI: 10.1007/s10571-021-01129-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 07/14/2021] [Indexed: 11/28/2022]
Abstract
Lithium (Li+) is a first option treatment for adult acute episodes of Bipolar Disorder (BD) and for the prophylaxis of new depressed or manic episodes. It is also the preferred choice as maintenance treatment. Numerous studies have shown morphological abnormalities in the brains of BD patients, suggesting that this highly heritable disorder may exhibit progressive and deleterious changes in brain structure. Since treatment with Li+ ameliorates these abnormalities, it has been postulated that Li+ is a neuroprotective agent in the same way atypical antipsychotics are neuroprotective in patients diagnosed with schizophrenia spectrum disorders. Li+'s neuroprotective properties are related to its modulation of nerve growth factors, inflammation, mitochondrial function, oxidative stress, and programmed cell death mechanisms such as autophagy and apoptosis. Notwithstanding, it is not known whether Li+-induced neuroprotection is related to the inhibition of its putative molecular targets in a BD episode: the enzymes inositol-monophosphatase, (IMPase), glycogen-synthase-kinase 3β (GSK3), and Protein kinase C (PKC). Furthermore, it is uncertain whether these neuroprotective mechanisms are correlated with Li+'s clinical efficacy in maintaining mood stability. It is expected that in a nearby future, precision medicine approaches will improve diagnosis and expand treatment options. This will certainly contribute to ameliorating the medical and economic burden created by this devastating mood disorder.
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Affiliation(s)
- Enrique L M Ochoa
- Department of Psychiatry and Behavioral Sciences, Volunteer Clinical Faculty, University of California at Davis, 2230 Stockton Boulevard, Sacramento, CA, 95817, USA.
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Piotrkowicz M, Janoska-Jazdzik M, Koweszko T, Szulc A. The Influence of Psychotherapy on Peripheral Brain-Derived Neurotrophic Factor Concentration Levels and Gene Methylation Status: A Systematic Review. J Clin Med 2021; 10:4424. [PMID: 34640441 PMCID: PMC8509187 DOI: 10.3390/jcm10194424] [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: 07/31/2021] [Revised: 09/23/2021] [Accepted: 09/24/2021] [Indexed: 01/02/2023] Open
Abstract
Psychotherapy is a well-established method of treating many mental disorders. It has been proven that psychotherapy leads to structural and functional changes in the brain; however, knowledge about the molecular and cellular mechanisms of these changes is limited. Neuroplasticity and one of its mediators, brain-derived neurotrophic factor (BDNF), are potential research targets in this field. To define the role of BDNF concentration in serum, or in plasma, and BDNF promoter gene methylation in saliva or leucocytes, in psychotherapy, an extensive literature search was conducted in the PubMed and Web of Science databases. The literature review was conducted based on papers published up until May 2021 that included pre and post psychotherapy measurements of either BDNF concentration levels or promoter gene methylation status. Ten studies were indicated as eligible for analysis: eight studies that investigated peripheral BDNF concentration levels, one study that investigated methylation status, and one study that included an evaluation of both subject matters. Patients underwent cognitive behavioral therapy or interpersonal psychotherapy. Patients were diagnosed with borderline personality disorder, major depressive disorder, anorexia nervosa, bulimia nervosa, or post-traumatic stress disorder. There were only three of the nine studies that showed statistically significant increases in BDNF concentration levels after psychotherapy. The two studies that involved BDNF gene methylation status showed a decrease in methylation after dialectical behavioral therapy of borderline patients.
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Affiliation(s)
- Michal Piotrkowicz
- Department of Psychiatry, Faculty of Health Sciences, Medical University of Warsaw, Partyzantow 2/4, 05-802 Pruszkow, Poland; (M.J.-J.); (T.K.); (A.S.)
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Ryu JS, Lee YM, Kim YS, Kang S, Park JS, Ahn CW, Nam JS, Seok JH. Association between BDNF Polymorphism and Depressive Symptoms in Patients Newly Diagnosed with Type 2 Diabetes Mellitus. Yonsei Med J 2021; 62:359-365. [PMID: 33779090 PMCID: PMC8007434 DOI: 10.3349/ymj.2021.62.4.359] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 01/05/2021] [Accepted: 01/26/2021] [Indexed: 01/01/2023] Open
Abstract
PURPOSE Little is known about the relationship between brain-derived neurotrophic factor (BDNF) gene polymorphisms and psychiatric symptoms in diabetes patients. We investigated the effects of BDNF Val/66/Met polymorphism, glucose status, psychological susceptibility, and resilience on anxiety and depression symptoms in patients newly diagnosed with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS We examined biochemical factors and BDNF polymorphism in 89 patients who were newly diagnosed with T2DM. Psychiatric symptoms were investigated with the Hospital Anxiety and Depression Scale (HADS), and the Connor-Davidson Resilience Scale (CD-RISC) and Impact of Event Scale (IES) were used to assess psychological resilience and susceptibility to psychological distress, respectively. Logistic regression analyses were conducted to investigate factors associated with psychiatric symptoms. RESULTS We determined that 62 patients (70%) were Met-carriers. No significant differences were found between the Val/Val homozygous and Met-carrier groups regarding age, sex, body mass index, and clinical factors related to glycemic control and lipid profiles. HADS-anxiety and HADS-depression scores and IES factor scores were higher in the Met-carrier than the Val/Val homozygous group. Hemoglobin A1c (HbA1c) level was significantly inversely correlated with the severity of depressive symptoms. Resilience factors showed significant inverse correlations, and IES factors showed positive correlations with depressive symptom severity. In the logistic regression analysis model, depressive symptoms were significantly associated with HbA1c and BDNF polymorphism, whereas only the hyperarousal factor of the IES scale was associated with anxiety. CONCLUSION Depressive symptoms are associated with the presence of the Met-carriers and lower HbA1c in patients newly diagnosed with T2DM.
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Affiliation(s)
- Jin Sun Ryu
- Department of Psychiatry, Yonsei University College of Medicine, Seoul, Korea
| | - Young Mi Lee
- Department of Internal Medicine, Dongtan Jeil Women's Hospital & Sangwoon Medical Institute, Hwasung, Korea
| | - Yu Sik Kim
- Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea
| | - Shinae Kang
- Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jong Suk Park
- Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Chul Woo Ahn
- Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Sun Nam
- Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
| | - Jeong Ho Seok
- Department of Psychiatry, Yonsei University College of Medicine, Seoul, Korea.
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Nakao A, Matsunaga Y, Hayashida K, Takahashi N. Role of Oxidative Stress and Ca 2+ Signaling in Psychiatric Disorders. Front Cell Dev Biol 2021; 9:615569. [PMID: 33644051 PMCID: PMC7905097 DOI: 10.3389/fcell.2021.615569] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 01/25/2021] [Indexed: 12/21/2022] Open
Abstract
Psychiatric disorders are caused by complex and diverse factors, and numerous mechanisms have been proposed for the pathogenesis of these disorders. Accumulating evidence suggests that oxidative stress is one of the general factors involved in the pathogenesis/pathophysiology of major psychiatric disorders, including bipolar disorder, depression, anxiety disorder, and schizophrenia. Indeed, some clinical trials have shown improvement of the symptoms of these disorders by antioxidant supplementation. However, the molecular basis for the relationship between oxidative stress and the pathogenesis of psychiatric disorders remains largely unknown. In general, Ca2+ channels play central roles in neuronal functions, including neuronal excitability, neurotransmitter release, synaptic plasticity, and gene regulation, and genes that encode Ca2+ channels have been found to be associated with psychiatric disorders. Notably, a class of Ca2+-permeable transient receptor potential (TRP) cation channels is activated by changes in cellular redox status, whereby these TRP channels can link oxidative stress to Ca2+ signals. Given the unique characteristic of redox-sensitive TRP channels, these channels could be a target for delineating the pathogenesis or pathophysiology of psychiatric disorders. In this review, we summarize the outcomes of clinical trials for antioxidant treatment in patients with psychiatric disorders and the current insights into the physiological/pathological significance of redox-sensitive TRP channels in the light of neural functions, including behavioral phenotypes, and discuss the potential role of TRP channels in the pathogenesis of psychiatric disorders. Investigation of redox-sensitive TRP channels may lead to the development of novel therapeutic strategies for the treatment of psychiatric disorders.
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Affiliation(s)
- Akito Nakao
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Yoshihiro Matsunaga
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Katsumi Hayashida
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Nobuaki Takahashi
- The Hakubi Center for Advanced Research, Kyoto University, Kyoto, Japan
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12
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de Las Heras B, Rodrigues L, Cristini J, Weiss M, Prats-Puig A, Roig M. Does the Brain-Derived Neurotrophic Factor Val66Met Polymorphism Modulate the Effects of Physical Activity and Exercise on Cognition? Neuroscientist 2020; 28:69-86. [PMID: 33300425 DOI: 10.1177/1073858420975712] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The Val66Met is a polymorphism of the brain-derived neurotrophic factor (BDNF) gene that encodes a substitution of a valine (Val) to methionine (Met) amino acid. Carrying this polymorphism reduces the activity-dependent secretion of the BDNF protein, which can potentially affect brain plasticity and cognition. We reviewed the biology of Val66Met and surveyed 26 studies (11,417 participants) that examined the role of this polymorphism in moderating the cognitive response to physical activity (PA) and exercise. Nine observational studies confirmed a moderating effect of Val66Met on the cognitive response to PA but differences between Val and Met carriers were inconsistent and only significant in some cognitive domains. Only five interventional studies found a moderating effect of Val66Met on the cognitive response to exercise, which was also inconsistent in its direction. Two studies showed a superior cognitive response in Val carriers and three studies showed a better response in Met carriers. These results do not support a general and consistent effect of Val66Met in moderating the cognitive response to PA or exercise. Both Val and Met carriers can improve specific aspects of cognition by increasing PA and engaging in exercise. Causes for discrepancies among studies, effect moderators, and future directions are discussed.
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Affiliation(s)
- Bernat de Las Heras
- Memory and Motor Rehabilitation Laboratory (MEMORY-LAB), Feil and Oberfeld Research Centre, Jewish Rehabilitation Hospital, Montreal Center for Interdisciplinary Research in Rehabilitation (CRIR), Laval, Quebec, Canada.,School of Physical and Occupational Therapy, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Lynden Rodrigues
- Memory and Motor Rehabilitation Laboratory (MEMORY-LAB), Feil and Oberfeld Research Centre, Jewish Rehabilitation Hospital, Montreal Center for Interdisciplinary Research in Rehabilitation (CRIR), Laval, Quebec, Canada.,School of Physical and Occupational Therapy, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Jacopo Cristini
- Memory and Motor Rehabilitation Laboratory (MEMORY-LAB), Feil and Oberfeld Research Centre, Jewish Rehabilitation Hospital, Montreal Center for Interdisciplinary Research in Rehabilitation (CRIR), Laval, Quebec, Canada.,School of Physical and Occupational Therapy, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Maxana Weiss
- Memory and Motor Rehabilitation Laboratory (MEMORY-LAB), Feil and Oberfeld Research Centre, Jewish Rehabilitation Hospital, Montreal Center for Interdisciplinary Research in Rehabilitation (CRIR), Laval, Quebec, Canada.,School of Physical and Occupational Therapy, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Anna Prats-Puig
- University School of Health and Sport (EUSES), University of Girona, Girona, Catalunya, Spain
| | - Marc Roig
- Memory and Motor Rehabilitation Laboratory (MEMORY-LAB), Feil and Oberfeld Research Centre, Jewish Rehabilitation Hospital, Montreal Center for Interdisciplinary Research in Rehabilitation (CRIR), Laval, Quebec, Canada.,School of Physical and Occupational Therapy, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
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13
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The biology of aggressive behavior in bipolar disorder: A systematic review. Neurosci Biobehav Rev 2020; 119:9-20. [DOI: 10.1016/j.neubiorev.2020.09.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 08/26/2020] [Accepted: 09/08/2020] [Indexed: 01/04/2023]
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14
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Rusciano I, Marvi MV, Owusu Obeng E, Mongiorgi S, Ramazzotti G, Follo MY, Zoli M, Morandi L, Asioli S, Fabbri VP, McCubrey JA, Suh PG, Manzoli L, Cocco L, Ratti S. Location-dependent role of phospholipase C signaling in the brain: Physiology and pathology. Adv Biol Regul 2020; 79:100771. [PMID: 33303387 DOI: 10.1016/j.jbior.2020.100771] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 11/16/2020] [Accepted: 11/25/2020] [Indexed: 12/13/2022]
Abstract
Phosphoinositide-specific phospholipases C (PI-PLCs) are a class of enzymes involved in the phosphatidylinositol metabolism, which is implicated in the activation of several signaling pathways and which controls several cellular processes. The scientific community has long accepted the existence of a nuclear phosphoinositide (PI) metabolism, independent from the cytoplasmic one, critical in nuclear function control. Indeed, nuclear PIs are involved in many activities, such as cell cycle regulation, cell proliferation, cell differentiation, membrane transport, gene expression and cytoskeletal dynamics. There are several types of PIs and enzymes implicated in brain activities and among these enzymes, PI-PLCs contribute to a specific and complex network in the developing nervous system. Moreover, considering the abundant presence of PI-PLCβ1, PI-PLCγ1 and PI-PLCβ4 in the brain, a specific role for each PLC subtype has been suggested in the control of neuronal activity, which is important for synapse function, development and other mechanisms. The focus of this review is to describe the latest research about the involvement of PI-PLC signaling in the nervous system, both physiologically and in pathological conditions. Indeed, PI-PLC signaling imbalance seems to be also linked to several brain disorders including epilepsy, movement and behavior disorders, neurodegenerative diseases and, in addition, some PI-PLC subtypes could become potential novel signature genes for high-grade gliomas.
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Affiliation(s)
- Isabella Rusciano
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Maria Vittoria Marvi
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Eric Owusu Obeng
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Sara Mongiorgi
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Giulia Ramazzotti
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Matilde Y Follo
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Matteo Zoli
- Center for the Diagnosis and Treatment of Hypothalamic-Pituitary Diseases - Pituitary Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna (Institute of Neurological Sciences of Bologna), Bologna, Italy; Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Italy
| | - Luca Morandi
- Functional MR Unit, Bellaria Hospital, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40139, Bologna, Italy
| | - Sofia Asioli
- Dipartimento di Scienze Biomediche e Neuromotorie, U.O.C. Anatomia Patologica, AUSL, Università di Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma Neurochirurgia Ipofisi, Bologna, Italy
| | - Viscardo Paolo Fabbri
- Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Italy
| | - James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
| | - Pann-Ghill Suh
- Korea Brain Research Institute, Daegu, Republic of Korea; School of Life Sciences, UNIST, Ulsan, Republic of Korea
| | - Lucia Manzoli
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Lucio Cocco
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Stefano Ratti
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
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15
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Miranda-Lourenço C, Ribeiro-Rodrigues L, Fonseca-Gomes J, Tanqueiro SR, Belo RF, Ferreira CB, Rei N, Ferreira-Manso M, de Almeida-Borlido C, Costa-Coelho T, Freitas CF, Zavalko S, Mouro FM, Sebastião AM, Xapelli S, Rodrigues TM, Diógenes MJ. Challenges of BDNF-based therapies: From common to rare diseases. Pharmacol Res 2020; 162:105281. [PMID: 33161136 DOI: 10.1016/j.phrs.2020.105281] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/20/2020] [Accepted: 10/22/2020] [Indexed: 12/11/2022]
Abstract
Neurotrophins are a well-known family of neurotrophic factors that play an important role both in the central and peripheral nervous systems, where they modulate neuronal survival, development, function and plasticity. Brain-derived neurotrophic factor (BDNF) possesses diverse biological functions which are mediated by the activation of two main classes of receptors, the tropomyosin-related kinase (Trk) B and the p75 neurotrophin receptor (p75NTR). The therapeutic potential of BDNF has drawn attention since dysregulation of its signalling cascades has been suggested to underlie the pathogenesis of both common and rare diseases. Multiple strategies targeting this neurotrophin have been tested; most have found obstacles that ultimately hampered their effectiveness. This review focuses on the involvement of BDNF and its receptors in the pathophysiology of Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Rett Syndrome (RTT). We describe the known mechanisms leading to the impairment of BDNF/TrkB signalling in these disorders. Such mechanistic insight highlights how BDNF signalling compromise can take various shapes, nearly disease-specific. Therefore, BDNF-based therapeutic strategies must be specifically tailored and are more likely to succeed if a combination of resources is employed.
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Affiliation(s)
- Catarina Miranda-Lourenço
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Leonor Ribeiro-Rodrigues
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - João Fonseca-Gomes
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Sara R Tanqueiro
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Rita F Belo
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Catarina B Ferreira
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Nádia Rei
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Mafalda Ferreira-Manso
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Carolina de Almeida-Borlido
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Tiago Costa-Coelho
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Céline Felicidade Freitas
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Svitlana Zavalko
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Francisco M Mouro
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Ana M Sebastião
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Sara Xapelli
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Tiago M Rodrigues
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Institute of Molecular and Clinical Ophthalmology Basel (IOB), Mittlere Strasse 91, 4031 Basel, Switzerland
| | - Maria J Diógenes
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal.
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16
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da Silveira Alves CF, Caumo W, Silvestri JM, Zortea M, Dos Santos VS, Cardoso DF, Regner A, de Souza AH, Simon D. Pain catastrophizing is associated with the Val66Met polymorphism of the brain-derived neurotrophic factor in fibromyalgia. Adv Rheumatol 2020; 60:39. [PMID: 32736598 DOI: 10.1186/s42358-020-00141-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 07/20/2020] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Fibromyalgia (FM) is a musculoskeletal chronic pain syndrome that impacts negatively patient's daily lives. Its pathogenesis is characterized by a complex relationship between biological and psychosocial factors not fully understood yet. Pain catastrophizing is associated with FM and is an important predictor of outcomes. This study aimed to answer two questions: (i) whether the allele and genotype frequencies of BDNF Val66Met (rs6265) polymorphism differs between FM patients and healthy controls (HC); and (ii) if the BDNF Val66Met polymorphism is a factor that predicts pain catastrophizing in FM. METHODS In a cross-sectional design, 108 FM patients and 108 HC were included. FM patients responded to the Brazilian Portuguese version of the Pain Catastrophizing Scale (BP-PCS) to assess pain catastrophizing, as well as other validated tools for anxiety (The State-Trait Anxiety Inventory - STAI), depression (Beck Depression Inventory II - BDI-II) and functional aspects (Fibromyalgia Impact Questionnaire - FIQ; Central Sensitization Inventory validated and adapted for Brazilian population - CSI-BP; Pittsburgh Sleep Quality Index - PSQI; and Resilience Scale). All subjects were genotyped for the BDNF Val66Met polymorphism. RESULTS Val allele was significantly more frequent in FM patients compared to the control group (p < 0.05). Also, FM patients with Val/Val genotype showed more pain catastrophizing thoughts, and this genotype was significantly associated with magnification and rumination dimensions of BP-PCS (p < 0.05). Furthermore, there were significant differences in levels of anxiety and symptoms of depression, years of education, and the functional situation between the FM and control groups. CONCLUSIONS The findings show an association of BDNF Val66Met polymorphism with pain catastrophizing in FM, which opens new avenues to comprehend the interplay between molecular genetic characteristics and neuroplasticity mechanisms underpinning FM.
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Affiliation(s)
- Camila Fernanda da Silveira Alves
- Graduate Program in Cellular and Molecular Biology Applied to Health, Universidade Luterana do Brasil (ULBRA), Av. Farroupilha, 8001 - Prédio 22 - 5° andar, Canoas, RS, 92425-900, Brazil.,Human Molecular Genetics Laboratory, Universidade Luterana do Brasil (ULBRA), Canoas, Brazil.,Laboratory of Pain and Neuromodulation at Hospital de Clinicas de Porto Alegre (HCPA), Porto Alegre, Brazil.,Graduate Program in Medical Sciences at Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Wolnei Caumo
- Laboratory of Pain and Neuromodulation at Hospital de Clinicas de Porto Alegre (HCPA), Porto Alegre, Brazil.,Graduate Program in Medical Sciences at Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.,Pain and Palliative Care Service, Hospital de Clínicas de Porto Alegre (HCPA); Department of Surgery, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Joana Morez Silvestri
- Human Molecular Genetics Laboratory, Universidade Luterana do Brasil (ULBRA), Canoas, Brazil
| | - Maxciel Zortea
- Laboratory of Pain and Neuromodulation at Hospital de Clinicas de Porto Alegre (HCPA), Porto Alegre, Brazil.,Graduate Program in Medical Sciences at Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Vinicius Souza Dos Santos
- Laboratory of Pain and Neuromodulation at Hospital de Clinicas de Porto Alegre (HCPA), Porto Alegre, Brazil.,Graduate Program in Medical Sciences at Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Dayane Favarin Cardoso
- Human Molecular Genetics Laboratory, Universidade Luterana do Brasil (ULBRA), Canoas, Brazil
| | - Andrea Regner
- Graduate Program in Cellular and Molecular Biology Applied to Health, Universidade Luterana do Brasil (ULBRA), Av. Farroupilha, 8001 - Prédio 22 - 5° andar, Canoas, RS, 92425-900, Brazil
| | - Alessandra Hübner de Souza
- Graduate Program in Cellular and Molecular Biology Applied to Health, Universidade Luterana do Brasil (ULBRA), Av. Farroupilha, 8001 - Prédio 22 - 5° andar, Canoas, RS, 92425-900, Brazil
| | - Daniel Simon
- Graduate Program in Cellular and Molecular Biology Applied to Health, Universidade Luterana do Brasil (ULBRA), Av. Farroupilha, 8001 - Prédio 22 - 5° andar, Canoas, RS, 92425-900, Brazil. .,Human Molecular Genetics Laboratory, Universidade Luterana do Brasil (ULBRA), Canoas, Brazil.
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17
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Nassan M, Veldic M, Winham S, Frye MA, Larrabee B, Colby C, Biernacka J, Bellia F, Pucci M, Terenius L, Vukojevic V, D'Addario C. Methylation of Brain Derived Neurotrophic Factor (BDNF) Val66Met CpG site is associated with early onset bipolar disorder. J Affect Disord 2020; 267:96-102. [PMID: 32063579 DOI: 10.1016/j.jad.2020.02.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 01/21/2020] [Accepted: 02/01/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND The brain-derived neurotrophic factor (BDNF) rs6265 (Val66Met) Met allele is associated with early onset (≤ 19 years old) bipolar disorder (BD). Val66Met (G196A) creates a CpG site when the Val/G allele is present. We sought to study the methylation of the BDNF promoter and its interaction with Val66Met genotype in BD. METHODS Sex/age-matched previously genotyped DNA samples from BD-Type 1 cases [N = 166: early onset (≤ 19 years old) n = 79, late onset (> 20 years old) n = 87] and controls (N = 162) were studied. Pyrosequencing of four CpGs in Promoter-I, four CpGs in promoter-IV, and two CpGs in Promoter-IX (CpG2 includes G= Val allele) was performed. Logistic regression adjusting for batch effect was used to compare cases vs. controls. Analyses also included stratification by disease onset and adjustment for Val66Met genotype. Secondary exploratory analyses for the association of life stressors, comorbid substance abuse, and psychotropic use with methylation patterns were performed. RESULTS Comparing all BD cases vs. controls and adjusting for Val66Met genotype, BD cases had significantly higher methylation in promoter -IX/CPG-2 (p = 0.0074). This was driven by early onset cases vs. controls (p = 0.00039) and not late onset cases vs. controls (p = 0.2). LIMITATION Relatively small sample size. CONCLUSION Early onset BD is associated with increased methylation of CpG site created by Val=G allele of the Val66Met variance. Further studies could include larger sample size and postmortem brain samples in an attempt to replicate these findings.
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Affiliation(s)
- Malik Nassan
- Mayo Clinic, Psychiatry & Psychology, Rochester, MN, USA
| | - Marin Veldic
- Mayo Clinic, Psychiatry & Psychology, Rochester, MN, USA
| | - Stacey Winham
- Mayo Clinic, Psychiatry & Psychology, Rochester, MN, USA
| | - Mark A Frye
- Mayo Clinic, Psychiatry & Psychology, Rochester, MN, USA
| | - Beth Larrabee
- Mayo Clinic, Psychiatry & Psychology, Rochester, MN, USA
| | - Colin Colby
- Mayo Clinic, Psychiatry & Psychology, Rochester, MN, USA
| | | | | | | | - Lars Terenius
- Karolinska Institute, Clinical Neuroscience, Solna, Sweden
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18
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Ghosh M, Ali A, Joshi S, Srivastava AS, Tapadia MG. SLC1A3 C3590T but not BDNF G196A is a predisposition factor for stress as well as depression, in an adolescent eastern Indian population. BMC MEDICAL GENETICS 2020; 21:53. [PMID: 32171272 PMCID: PMC7071583 DOI: 10.1186/s12881-020-0993-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 03/04/2020] [Indexed: 01/19/2023]
Abstract
Background Adolescence is a distinctive stage of various changes and is noted as peak age for onset of many psychiatric disorders, especially linked to stress and depression. Several genetic variations are being increasingly known to be linked with stress and depression. The polymorphisms in two such genes, the BDNF and SLC1A3, have been reported to be linked with either depression/stress or with suicidal behaviour. These genes have not been validated in Indian population, and therefore there is a need to investigate these genes in Indian population. The present study was undertaken to test whether the known polymorphisms SLC1A3 C3590T, SLC1A3 C869G and BDNF G196A are associated or not with stress or depression in an eastern Indian population. Methods A case-control association study was performed with 108 cases having variable levels of stress and depression and 205 matched controls. Detection of stress and depression was done by using standard instruments as PSS and CES-D, respectively and demographic profile was obtained for each individual on the basis of personal data sheet. Genotyping for the selected polymorphisms was performed by PCR followed by restriction digestion. Results The SNP SLC1A3 C3590T was found to be associated with stress and depression (p = 0.0042, OR = 2.072). Therefore, the T allele increases the risk by more than two folds for stress and depression in the present population. The other allele of SLC1A3, G869C, as well as BDNF G196A were not associated with stress or depression in the population studied. Conclusion SLC1A3 C3590T is a predisposition factor for stress and depression in an eastern Indian population, whereas SLC1A3 G869C and BDNF G196A were not found to be a risk factor. Therefore, presence of T allele of SLC1A3 C3590T, may predict the development of stress and depression in an individual. This may also help in the understanding of pathophysiology of the disease. However, these findings warrant a wider study in Indian populations and would be of significance in understanding the predisposition of stress and depression in this population.
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Affiliation(s)
- Madhumita Ghosh
- Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, 221005, India
| | - Akhtar Ali
- Centre for Genetic Disorders, Faculty of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Shobhna Joshi
- Department of Psychology, Faculty of Arts, Banaras Hindu University, Varanasi, 221005, India
| | - Adya Shankar Srivastava
- Department of Psychiatry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Madhu G Tapadia
- Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, 221005, India.
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19
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Schröter K, Brum M, Brunkhorst-Kanaan N, Tole F, Ziegler C, Domschke K, Reif A, Kittel-Schneider S. Longitudinal multi-level biomarker analysis of BDNF in major depression and bipolar disorder. Eur Arch Psychiatry Clin Neurosci 2020; 270:169-181. [PMID: 30929061 DOI: 10.1007/s00406-019-01007-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Accepted: 03/22/2019] [Indexed: 12/15/2022]
Abstract
Preliminary evidence suggests that BDNF (brain derived neurotrophic factor) rs6265 genetic polymorphism, BDNF gene promotor methylation and BDNF serum levels might play an important role in the pathogenesis of affective disorders. As studies testing the BDNF system across molecular levels are sparse, this study aimed at investigating the BDNF val66met genotype, BDNF DNA methylation changes and peripheral BDNF serum levels in acute and remitted phases of MDD (major depressive disorder) and BD (bipolar disorder) and healthy controls. We found a significant difference of methylation levels at CpG site 1-1-1 and 3-1-1 between MDD and healthy controls (p < 0.003) with MDD patients showing significantly higher methylation levels. CpG 5-2-1 revealed a statistically significant difference between MDD and healthy controls and MDD and BD (p = 0.00003). Similar to the results of the methylation analysis a significant difference between MDD and healthy controls was found in BDNF serum levels (p = 0.002) with significantly lower BDNF serum levels in MDD compared to healthy controls. A difference between the samples from admission and discharge from hospital of both BDNF gene methylation and serum levels could not be detected in the present study and no influence of the BDNF val66met genotype on neither methylation nor BDNF serum level.
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Affiliation(s)
- Katrin Schröter
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Heinrich-Hoffmann-Str. 10, 60528, Frankfurt, Germany
| | - Murielle Brum
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Heinrich-Hoffmann-Str. 10, 60528, Frankfurt, Germany
| | - Nathalie Brunkhorst-Kanaan
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Heinrich-Hoffmann-Str. 10, 60528, Frankfurt, Germany
| | - Franziska Tole
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Heinrich-Hoffmann-Str. 10, 60528, Frankfurt, Germany
| | - Christiane Ziegler
- Department of Psychiatry and Psychotherapy, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Katharina Domschke
- Department of Psychiatry and Psychotherapy, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Andreas Reif
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Heinrich-Hoffmann-Str. 10, 60528, Frankfurt, Germany
| | - Sarah Kittel-Schneider
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Heinrich-Hoffmann-Str. 10, 60528, Frankfurt, Germany.
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20
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Orsolini L, Latini R, Pompili M, Serafini G, Volpe U, Vellante F, Fornaro M, Valchera A, Tomasetti C, Fraticelli S, Alessandrini M, La Rovere R, Trotta S, Martinotti G, Di Giannantonio M, De Berardis D. Understanding the Complex of Suicide in Depression: from Research to Clinics. Psychiatry Investig 2020; 17:207-221. [PMID: 32209966 PMCID: PMC7113180 DOI: 10.30773/pi.2019.0171] [Citation(s) in RCA: 203] [Impact Index Per Article: 40.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 02/27/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE Amongst psychiatric disorders, major depressive disorder (MDD) is the most prevalent, by affecting approximately 15-17% of the population and showing a high suicide risk rate equivalent to around 15%. The present comprehensive overview aims at evaluating main research studies in the field of MDD at suicide risk, by proposing as well as a schematic suicide risk stratification and useful flow-chart for planning suicide preventive and therapeutic interventions for clinicians. METHODS A broad and comprehensive overview has been here conducted by using PubMed/Medline, combining the search strategy of free text terms and exploded MESH headings for the topics of 'Major Depressive Disorder' and 'Suicide' as following: ((suicide [Title/Abstract]) AND (major depressive disorder [Title/Abstract])). All articles published in English through May 31, 2019 were summarized in a comprehensive way. RESULTS Despite possible pathophysiological factors which may explain the complexity of suicide in MDD, scientific evidence supposed the synergic role of genetics, exogenous and endogenous stressors (i.e., interpersonal, professional, financial, as well as psychiatric disorders), epigenetic, the hypothalamic-pituitary-adrenal stress-response system, the involvement of the monoaminergic neurotransmitter systems, particularly the serotonergic ones, the lipid profile, neuro-immunological biomarkers, the Brain-derived neurotrophic factor and other neuromodulators. CONCLUSION The present overview reported that suicide is a highly complex and multifaceted phenomenon in which a large plethora of mechanisms could be variable implicated, particularly amongst MDD subjects. Beyond these consideration, modern psychiatry needs a better interpretation of suicide risk with a more careful assessment of suicide risk stratification and planning of clinical and treatment interventions.
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Affiliation(s)
- Laura Orsolini
- Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK.,Neomesia Mental Health, Villa Jolanda Hospital, Jesi, Italy.,Polyedra, Teramo, Italy
| | - Roberto Latini
- Neomesia Mental Health, Villa Jolanda Hospital, Jesi, Italy
| | - Maurizio Pompili
- Department of Neurosciences, Mental Health and Sensory Organs, Suicide Prevention Center, S. Andrea Hospital, Sapienza University, Rome, Italy
| | - Gianluca Serafini
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Psychiatry, University of Genoa, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Umberto Volpe
- Department of Clinical Neurosciences/DIMSC, School of Medicine, Section of Psychiatry, Polytechnic University of Marche, Ancona, Italy
| | - Federica Vellante
- Department of Neuroscience, Imaging and Clinical Science, Chair of Psychiatry, University of "G. D'Annunzio", Chieti, Italy
| | - Michele Fornaro
- Polyedra, Teramo, Italy.,Department of Psychiatry, Federico II University, Naples, Italy
| | - Alessandro Valchera
- Polyedra, Teramo, Italy.,Villa S. Giuseppe Hospital, Hermanas Hospitalarias, Ascoli Piceno, Italy
| | - Carmine Tomasetti
- Department of Mental Health, National Health Service, Psychiatric Service of Diagnosis and Treatment, Hospital "SS. Annunziata" ASL 4, Giulianova, Italy
| | - Silvia Fraticelli
- Department of Neuroscience, Imaging and Clinical Science, Chair of Psychiatry, University of "G. D'Annunzio", Chieti, Italy
| | - Marco Alessandrini
- Department of Neuroscience, Imaging and Clinical Science, Chair of Psychiatry, University of "G. D'Annunzio", Chieti, Italy
| | - Raffaella La Rovere
- Department of Mental Health, National Health Service, Azienda Sanitaria Locale, Pescara, Italy
| | - Sabatino Trotta
- Department of Mental Health, National Health Service, Azienda Sanitaria Locale, Pescara, Italy
| | - Giovanni Martinotti
- Department of Neuroscience, Imaging and Clinical Science, Chair of Psychiatry, University of "G. D'Annunzio", Chieti, Italy
| | - Massimo Di Giannantonio
- Department of Neuroscience, Imaging and Clinical Science, Chair of Psychiatry, University of "G. D'Annunzio", Chieti, Italy
| | - Domenico De Berardis
- Department of Neuroscience, Imaging and Clinical Science, Chair of Psychiatry, University of "G. D'Annunzio", Chieti, Italy.,Department of Mental Health, National Health Service, Psychiatric Service of Diagnosis and Treatment, Hospital "G. Mazzini", ASL 4, Teramo, Italy
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21
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Khani-Habibabadi F, Askari S, Zahiri J, Javan M, Behmanesh M. Novel BDNF-regulatory microRNAs in neurodegenerative disorders pathogenesis: An in silico study. Comput Biol Chem 2019; 83:107153. [PMID: 31751881 DOI: 10.1016/j.compbiolchem.2019.107153] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 10/13/2019] [Accepted: 10/16/2019] [Indexed: 11/28/2022]
Abstract
Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor with various roles in the central nervous system neurogenesis, neuroprotection, and axonal guide. By attaching to Tropomyosin receptor kinase B (TrkB) receptor, this protein triggers downstream signaling pathways which lead to cellular growth, proliferation, survival, and neuroplasticity. Deregulation at mRNA level is involved in various central nervous system disorders including, Huntington, Alzheimer's, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis diseases. Considering the importance of BDNF functions, deciphering the regulatory mechanisms controlling BDNF expression level could pave the way to develop more accurate and efficient treatments for neurological diseases. Among different regulatory systems, microRNAs (miRNAs) play prominent roles by targeting genes 3' untranslated regions. In this study, 127 validated and bioinformatic-predicted miRNAs with potentially regulatory roles in BDNF expression were analyzed. Various aspects of miRNAsö possible functions were assessed by bioinformatic online tools to find their potential regulatory functions in signaling pathways, neurological disorders, expression of transcription factors and miRNAs sponge. Analyzed data led to introduce 5 newly reported miRNAs that could regulate BDNF expression level. Finally, high throughput sequencing data from different brain regions and neurological disorders were analyzed to measure correlation of candidate miRNAs with BDNF level in experimental studies. In this study, a list of novel miRNAs with possible regulatory roles in BDNF expression level involving in different neurological disorders was introduced.
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Affiliation(s)
- Fatemeh Khani-Habibabadi
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Shahrzad Askari
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Javad Zahiri
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Javan
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mehrdad Behmanesh
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
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22
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Jones RM, Pattwell SS. Future considerations for pediatric cancer survivorship: Translational perspectives from developmental neuroscience. Dev Cogn Neurosci 2019; 38:100657. [PMID: 31158802 PMCID: PMC6697051 DOI: 10.1016/j.dcn.2019.100657] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 04/26/2019] [Accepted: 05/06/2019] [Indexed: 02/06/2023] Open
Abstract
Breakthroughs in modern medicine have increased pediatric cancer survival rates throughout the last several decades. Despite enhanced cure rates, a subset of pediatric cancer survivors exhibit life-long psychological side effects. A large body of work has addressed potential mechanisms for secondary symptoms of anxiety, post-traumatic stress, impaired emotion regulation and cognitive deficits in adults. Yet, absent from many studies are the ways in which cancer treatment can impact the developing brain. Additionally, it remains less known whether typical neurobiological changes during adolescence and early adulthood may potentially buffer or exacerbate some of the known negative cancer survivorship outcomes. This review highlights genetic, animal, and human neuroimaging research across development. We focus on the neural circuitry associated with aversive learning, which matures throughout childhood, adolescence and early adulthood. We argue that along with other individual differences, the precise timing of oncological treatment insults on such neural circuitry may expose particular vulnerabilities for pediatric cancer patients. We also explore other moderators of treatment outcomes, including genetic polymorphisms and neural mechanisms underlying memory and cognitive control. We discuss how neural maturation extending into young adulthood may also provide a sensitive period for intervention to improve psychological and cognitive outcomes in pediatric cancer survivors.
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Affiliation(s)
- Rebecca M Jones
- The Sackler Institute for Developmental Psychobiology, Department of Psychiatry, Weill Cornell Medicine, New York, NY 10065, United States
| | - Siobhan S Pattwell
- Human Biology Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mailstop C3-168, Seattle, WA 98109, United States.
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23
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Pagani R, Gasparini A, Ielmini M, Caselli I, Poloni N, Ferrari M, Marino F, Callegari C. Twenty years of Lithium pharmacogenetics: A systematic review. Psychiatry Res 2019; 278:42-50. [PMID: 31146140 DOI: 10.1016/j.psychres.2019.05.036] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 05/21/2019] [Accepted: 05/21/2019] [Indexed: 01/31/2023]
Abstract
Lithium is among the best proven treatments for patients diagnosed with Bipolar Disorder, however response to Lithium appears to be considerably variable among individuals and it has been suggested that this inconstancy in Lithium response could be genetically determined. Starting from this perspective, in the last few decades, a number of pharmacogenetic studies have attempted to identify genetic variants, which might be associated with response to Lithium in bipolar patients, in order to develop a pharmacogenetics test to tailor treatment on patients, identifying who will benefit the most from therapy with Lithium. Within this context, authors have critically reviewed pharmacogenetic studies of Lithium response in bipolar disorder, suggesting strategies for future work in this field. Computerized searches of PubMed and Embase databases, for studies published between 1998 and January 2018, was performed: 1162 studies were identified but only 37 relevant papers were selected for detailed review. Despite some interesting preliminary findings, the pharmacogenetics of Lithium and the development of a specific pharmacogenetics test in bipolar disorder appears to be a field still in its infancy, even though the advent of genome-wide association studies holds particular promise for future studies, which should include larger samples.
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Affiliation(s)
- R Pagani
- Clinica Santa Croce, Orselina, Switzerland
| | - A Gasparini
- Department of Medicine and Surgery, Division of Psychiatry, University of Insubria, Viale Borri 57, 2100 Varese, Italy
| | - M Ielmini
- Department of Medicine and Surgery, Division of Psychiatry, University of Insubria, Viale Borri 57, 2100 Varese, Italy
| | - I Caselli
- Department of Medicine and Surgery, Division of Psychiatry, University of Insubria, Viale Borri 57, 2100 Varese, Italy
| | - N Poloni
- Department of Medicine and Surgery, Division of Psychiatry, University of Insubria, Viale Borri 57, 2100 Varese, Italy
| | - M Ferrari
- Department of Clinical Medicine, Division of Experimental and Clinical Pharmacology, University of Insubria, Varese, Italy
| | - F Marino
- Department of Clinical Medicine, Division of Experimental and Clinical Pharmacology, University of Insubria, Varese, Italy
| | - C Callegari
- Department of Medicine and Surgery, Division of Psychiatry, University of Insubria, Viale Borri 57, 2100 Varese, Italy.
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24
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Nestor PG, O'Donovan K, Lapp HE, Hasler VC, Boodai SB, Hunter R. Risk and protective effects of serotonin and BDNF genes on stress-related adult psychiatric symptoms. Neurobiol Stress 2019; 11:100186. [PMID: 31440532 PMCID: PMC6700400 DOI: 10.1016/j.ynstr.2019.100186] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 06/19/2019] [Accepted: 07/04/2019] [Indexed: 12/14/2022] Open
Abstract
We focused on individual risk by examining childhood adversity and current psychiatric symptoms in a sample of 100 college students genotyped for both the serotonin transporter (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF). Naturally occurring allelic variation in 5-HTTLPR (short/long) and BDNF (valine/methionine) have been strongly implicated in stress-related psychiatric risk, but the combined effects of these alleles on psychological functioning have yet to be fully elucidated. Univariate analysis revealed gene-environment correlations linking heightened psychiatric risk with past childhood adversity for short but not long 5-HTTLPR allelic carriers and for valine (Val) but not methionine (Met) BDNF allelic carriers. Multivariate analyses revealed a significant gene x gene interaction with results showing that risk varied systematically depending on both 5-HTTLPR and BDNF alleles, independent of childhood adversity. Hierarchical regression analyses indicated that approximately 11% of the variance in symptoms of depression could be specifically accounted for by the epistatic interaction of 5-HTTLPR and BDNF val66Met polymorphisms. Allelic group analyses indicated lowest risk, as measured by depression and anxiety, for allelic carriers of 5-HTTLPR-short and BDNF Met, followed by 5-HTTLPR-long and BDNF-Val, 5-HTTLPR-short and BDNF-Val, and 5-HTTLPR-long and BDNF-Met. Results suggest that protective or risk-enhancing effects on stress-related psychiatric functioning may depend on specific allelic combinations of 5-HTTLPR and BDNF.
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25
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Nascimento C, Nunes VP, Diehl Rodriguez R, Takada L, Suemoto CK, Grinberg LT, Nitrini R, Lafer B. A review on shared clinical and molecular mechanisms between bipolar disorder and frontotemporal dementia. Prog Neuropsychopharmacol Biol Psychiatry 2019; 93:269-283. [PMID: 31014945 PMCID: PMC6994228 DOI: 10.1016/j.pnpbp.2019.04.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 04/15/2019] [Accepted: 04/18/2019] [Indexed: 12/12/2022]
Abstract
Mental disorders are highly prevalent and important causes of medical burden worldwide. Co-occurrence of neurological and psychiatric symptoms are observed among mental disorders, representing a challenge for their differential diagnosis. Psychiatrists and neurologists have faced challenges in diagnosing old adults presenting behavioral changes. This is the case for early frontotemporal dementia (FTD) and bipolar disorder. In its initial stages, FTD is characterized by behavioral or language disturbances in the absence of cognitive symptoms. Consequently, patients with the behavioral subtype of FTD (bv-FTD) can be initially misdiagnosed as having a psychiatric disorder, typically major depression disorder (MDD) or bipolar disorder (BD). Bipolar disorder is associated with a higher risk of dementia in older adults and with cognitive impairment, with a subset of patients presents a neuroprogressive pattern during the disease course. No mendelian mutations were identified in BD, whereas three major genetic causes of FTD have been identified. Clinical similarities between BD and bv-FTD raise the question whether common molecular pathways might explain shared clinical symptoms. Here, we reviewed existing data on clinical and molecular similarities between BD and FTD to propose biological pathways that can be further investigated as common or specific markers of BD and FTD.
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Affiliation(s)
- Camila Nascimento
- Bipolar Disorder Program (PROMAN), Department of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil.
| | - Villela Paula Nunes
- Bipolar Disorder Program (PROMAN), Department of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil.
| | - Roberta Diehl Rodriguez
- Behavioral and Cognitive Neurology Unit, Department of Neurology and LIM 22, University of São Paulo, São Paulo 05403-900, Brazil
| | - Leonel Takada
- Behavioral and Cognitive Neurology Unit, Department of Neurology, University of São Paulo, São Paulo 05403-900, Brazil
| | - Cláudia Kimie Suemoto
- Division of Geriatrics, LIM-22, University of São Paulo Medical School, São Paulo 01246-90, Brazil
| | - Lea Tenenholz Grinberg
- Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo 01246-90, Brazil; Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94143-120, USA.
| | - Ricardo Nitrini
- Behavioral and Cognitive Neurology Unit, Department of Neurology, University of São Paulo, São Paulo 05403-900, Brazil
| | - Beny Lafer
- Bipolar Disorder Program (PROMAN), Department of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil
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26
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McGregor CE, Irwin AM, English AW. The Val66Met BDNF Polymorphism and Peripheral Nerve Injury: Enhanced Regeneration in Mouse Met-Carriers Is Not Further Improved With Activity-Dependent Treatment. Neurorehabil Neural Repair 2019; 33:407-418. [PMID: 31068076 DOI: 10.1177/1545968319846131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Activity-dependent treatments to enhance peripheral nerve regeneration after injury have shown great promise, and clinical trials implementing them have begun. Success of these treatments requires activity-dependent release of brain-derived neurotrophic factor (BDNF). A single nucleotide polymorphism (SNP) in the bdnf gene known as Val66Met, which is found in nearly one third of the human population, results in defective activity-dependent BDNF secretion and could impact the effectiveness of these therapies. Here, we used a mouse model of this SNP to test the efficacy of treadmill exercise in enhancing axon regeneration in animals both heterozygous (V/M) and homozygous (M/M) for the SNP. Axon regeneration was studied 4 weeks after complete transection and repair of the sciatic nerve in both male and female animals, using both electrophysiological and histological outcome measures. Regeneration was enhanced significantly without treatment in V/M mice, compared with wild type (V/V) controls. Unlike V/V mice, treatment of both V/M and M/M mice with treadmill exercise did not result in enhanced regeneration. These results were recapitulated in vitro using dissociated neurons containing the light-sensitive cation channel, channelrhodopsin. Three days after plating, neurites of neurons from V/M and M/M mice were longer than those of V/V neurons. In neurons from V/V mice, but not those from V/M or M/M animals, longer neurites were found after optogenetic stimulation. Taken together, Met-carriers possess an intrinsically greater capacity to regenerate axons in peripheral nerves, but this cannot be enhanced further by activity-dependent treatments.
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27
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Rao S, Han X, Shi M, Siu CO, Waye MMY, Liu G, Wing YK. Associations of the serotonin transporter promoter polymorphism (5-HTTLPR) with bipolar disorder and treatment response: A systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 2019; 89:214-226. [PMID: 30217771 DOI: 10.1016/j.pnpbp.2018.08.035] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 08/30/2018] [Accepted: 08/31/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Associations of the serotonin transporter promoter polymorphism (5-HTTLPR) with bipolar disorder (BPD) and treatment response in bipolar patients were not conclusive. This study not only assessed the association between the 5-HTTLPR and BPD with accumulating relevant studies, but also in the first time evaluated the effect of the 5-HTTLPR on both anti-depressive and anti-manic treatment responses in bipolar patients. METHODS PubMed, Embase, PsycINFO, Cochrane Library and Cochrane Control Trials databases were systematically searched before February 2017. This meta-analysis followed the PRISMA guidelines. RESULTS A total of 32 population-based studies (5567 cases and 6993 controls) and 9 family-based studies (837 trios) were finally screened out and statistically joined into a single meta-analysis that revealed an association between S allele and an increased risk of BPD (OR = 1.06, p = .038). Pooled analysis of the 32 population-based studies indicated an association of S-carrier genotypes with an increased risk of BPD (OR = 1.10, p = .029). Meanwhile, the association remained significant in Caucasians (OR = 1.15, p = .004), which could provide an enough power (88%) to detect a significant association. Regarding the treatment response studies, 6 studies reporting the relationship of the 5-HTTLPR in anti-depressive remission rate (1034 patients) and 7 studies reporting in response rate (1098 patients) were included for pooled analyses. We observed a significant association of S-carrier genotypes with a reduced anti-depressive remission rate (OR = 0.64, p = .006) but not with anti-depressive response rate. The association between the 5-HTTLPR with anti-manic response rate was not observed in the included 6 studies (676 patients). CONCLUSIONS The present study supported the presence of a marginal but detectable effect of the 5-HTTLPR on susceptibility to BPD. Moreover, the detected association in Caucasian was statistically reliable. Besides, the 5-HTTLPR was identified as a useful predictor for anti-depressive remission but not for anti-depressive or anti-manic response.
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Affiliation(s)
- Shitao Rao
- Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, N.T., Hong Kong, SAR, China; The Nethersole School of Nursing, Faculty of Medicine, The Chinese University of Hong Kong, N.T., Hong Kong, SAR, China
| | - Xinyu Han
- The Nethersole School of Nursing, Faculty of Medicine, The Chinese University of Hong Kong, N.T., Hong Kong, SAR, China; College of Food and Biological Engineering, Jimei University, Xiamen, Fujian, China
| | - Mai Shi
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, N.T., Hong Kong, SAR, China
| | - Cynthia O Siu
- COS & Associates Ltd., Central District, Hong Kong, SAR, China
| | - Mary Miu Yee Waye
- The Nethersole School of Nursing, Faculty of Medicine, The Chinese University of Hong Kong, N.T., Hong Kong, SAR, China
| | - Guangming Liu
- College of Food and Biological Engineering, Jimei University, Xiamen, Fujian, China.
| | - Yun Kwok Wing
- Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, N.T., Hong Kong, SAR, China.
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28
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Kirli U, Binbay T, Drukker M, Elbi H, Kayahan B, Gökçelli DK, Özkınay F, Onay H, Alptekin K, van Os J. Is BDNF-Val66Met polymorphism associated with psychotic experiences and psychotic disorder outcome? Evidence from a 6 years prospective population-based cohort study. Am J Med Genet B Neuropsychiatr Genet 2019; 180:113-121. [PMID: 29785763 DOI: 10.1002/ajmg.b.32641] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 04/05/2018] [Accepted: 04/23/2018] [Indexed: 12/19/2022]
Abstract
There is little research on genetic risk for the extended psychosis phenotype ranging from psychotic experiences (PEs) to psychotic disorders (PDs). In this general population-based prospective cohort study, the longitudinal associations between BDNF-Val66Met polymorphism and the different levels of the extended psychosis phenotype were investigated. Addresses were contacted in a multistage clustered probability sampling frame covering 11 districts and 302 neighborhoods at baseline (n = 4011). A nested case-control study (n = 366) recruited individuals with PEs and PDs as well as individuals with no psychotic symptoms. In this subgroup, blood sampling for genetic analysis and assessment of environmental exposures were carried out, followed by clinical re-appraisal at follow-up 6 years later (n = 254). The BDNF-Val66Met polymorphism was significantly associated with the extended psychosis phenotype. The pattern of the association was that the BDNF-Val66Met polymorphism impacted in a dose-response but extra-linear fashion, with stronger impact at the PD end of the extended psychosis phenotype. Associations were still significant after adjusting for sociodemographic factors and environmental exposures including life events, childhood adversity, socioeconomic status, urbanicity, and cannabis use. The BDNF-Val66Met polymorphism may index susceptibility to expression of psychosis along a spectrum.
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Affiliation(s)
- Umut Kirli
- Department of Psychiatry, Van Education and Research Hospital, Van, Turkey.,School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Psychology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Tolga Binbay
- Faculty of Medicine, Department of Psychiatry, Dokuz Eylül University, Izmir, Turkey
| | - Marjan Drukker
- School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Psychology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Hayriye Elbi
- Faculty of Medicine, Department of Psychiatry, Ege University, Izmir, Turkey
| | - Bülent Kayahan
- Faculty of Medicine, Department of Psychiatry, Ege University, Izmir, Turkey
| | | | - Ferda Özkınay
- Faculty of Medicine, Department of Medical Genetics, Ege University, Izmir, Turkey
| | - Hüseyin Onay
- Faculty of Medicine, Department of Medical Genetics, Ege University, Izmir, Turkey
| | - Köksal Alptekin
- Faculty of Medicine, Department of Psychiatry, Dokuz Eylül University, Izmir, Turkey
| | - Jim van Os
- School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Psychology, Maastricht University Medical Centre, Maastricht, The Netherlands.,Department of Psychosis Studies, Institute of Psychiatry, King's College, King's Health Partners, London, United Kingdom.,Department of Psychiatry, Brain Centre Rudolf Magnus, Utrecht University Medical Centre, Utrecht, The Netherlands
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29
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McGregor CE, English AW. The Role of BDNF in Peripheral Nerve Regeneration: Activity-Dependent Treatments and Val66Met. Front Cell Neurosci 2019; 12:522. [PMID: 30687012 PMCID: PMC6336700 DOI: 10.3389/fncel.2018.00522] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 12/14/2018] [Indexed: 11/29/2022] Open
Abstract
Despite the ability of peripheral nerves to spontaneously regenerate after injury, recovery is generally very poor. The neurotrophins have emerged as an important modulator of axon regeneration, particularly brain derived neurotrophic factor (BDNF). BDNF regulation and signaling, as well as its role in activity-dependent treatments including electrical stimulation, exercise, and optogenetic stimulation are discussed here. The importance of a single nucleotide polymorphism in the BDNF gene, Val66Met, which is present in 30% of the human population and may hinder the efficacy of these treatments in enhancing regeneration after injury is considered. Preliminary data are presented on the effectiveness of one such activity-dependent treatment, electrical stimulation, in enhancing axon regeneration in mice expressing the met allele of the Val66Met polymorphism.
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Affiliation(s)
- Claire Emma McGregor
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, United States
| | - Arthur W English
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, United States
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30
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Yip SW, Potenza MN. Application of Research Domain Criteria to childhood and adolescent impulsive and addictive disorders: Implications for treatment. Clin Psychol Rev 2018; 64:41-56. [PMID: 27876165 PMCID: PMC5423866 DOI: 10.1016/j.cpr.2016.11.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Revised: 03/18/2016] [Accepted: 11/07/2016] [Indexed: 12/30/2022]
Abstract
The Research Domain Criteria (RDoC) initiative provides a large-scale, dimensional framework for the integration of research findings across traditional diagnoses, with the long-term aim of improving existing psychiatric treatments. A neurodevelopmental perspective is essential to this endeavor. However, few papers synthesizing research findings across childhood and adolescent disorders exist. Here, we discuss how the RDoC framework may be applied to the study of childhood and adolescent impulsive and addictive disorders in order to improve neurodevelopmental understanding and to enhance treatment development. Given the large scope of RDoC, we focus on a single construct highly relevant to addictive and impulsive disorders - initial responsiveness to reward attainment. Findings from genetic, molecular, neuroimaging and other translational research methodologies are highlighted.
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Affiliation(s)
- Sarah W Yip
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States; The National Center on Addiction and Substance Abuse, Yale University School of Medicine, New Haven, CT, United States
| | - Marc N Potenza
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States; The National Center on Addiction and Substance Abuse, Yale University School of Medicine, New Haven, CT, United States; Child Study Center, Yale University School of Medicine, New Haven, CT, United States; Department of Neurobiology, Yale University School of Medicine, New Haven, CT, United States.
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31
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Ghasemi M, Claunch J, Niu K. Pathologic role of nitrergic neurotransmission in mood disorders. Prog Neurobiol 2018; 173:54-87. [PMID: 29890213 DOI: 10.1016/j.pneurobio.2018.06.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 05/30/2018] [Accepted: 06/05/2018] [Indexed: 02/08/2023]
Abstract
Mood disorders are chronic, recurrent mental diseases that affect millions of individuals worldwide. Although over the past 40 years the biogenic amine models have provided meaningful links with the clinical phenomena of, and the pharmacological treatments currently employed in, mood disorders, there is still a need to examine the contribution of other systems to the neurobiology and treatment of mood disorders. This article reviews the current literature describing the potential role of nitric oxide (NO) signaling in the pathophysiology and thereby the treatment of mood disorders. The hypothesis has arisen from several observations including (i) altered NO levels in patients with mood disorders; (ii) antidepressant effects of NO signaling blockers in both clinical and pre-clinical studies; (iii) interaction between conventional antidepressants/mood stabilizers and NO signaling modulators in several biochemical and behavioral studies; (iv) biochemical and physiological evidence of interaction between monoaminergic (serotonin, noradrenaline, and dopamine) system and NO signaling; (v) interaction between neurotrophic factors and NO signaling in mood regulation and neuroprotection; and finally (vi) a crucial role for NO signaling in the inflammatory processes involved in pathophysiology of mood disorders. These accumulating lines of evidence have provided a new insight into novel approaches for the treatment of mood disorders.
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Affiliation(s)
- Mehdi Ghasemi
- Department of Neurology, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
| | - Joshua Claunch
- Department of Neurology, University of Massachusetts Medical School, Worcester, MA, 01655, USA
| | - Kathy Niu
- Department of Neurology, University of Massachusetts Medical School, Worcester, MA, 01655, USA
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Tsai SJ. Critical Issues in BDNF Val66Met Genetic Studies of Neuropsychiatric Disorders. Front Mol Neurosci 2018; 11:156. [PMID: 29867348 PMCID: PMC5962780 DOI: 10.3389/fnmol.2018.00156] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 04/24/2018] [Indexed: 12/20/2022] Open
Abstract
Neurotrophins have been implicated in the pathophysiology of many neuropsychiatric diseases. Brain-derived neurotrophic factor (BDNF) is the most abundant and widely distributed neurotrophin in the brain. Its Val66Met polymorphism (refSNP Cluster Report: rs6265) is a common and functional single-nucleotide polymorphism (SNP) affecting the activity-dependent release of BDNF. BDNF Val66Met transgenic mice have been generated, which may provide further insight into the functional impact of this polymorphism in the brain. Considering the important role of BDNF in brain function, more than 1,100 genetic studies have investigated this polymorphism in the past 15 years. Although these studies have reported some encouraging positive findings initially, most of the findings cannot be replicated in following studies. These inconsistencies in BDNF Val66Met genetic studies may be attributed to many factors such as age, sex, environmental factors, ethnicity, genetic model used for analysis, and gene–gene interaction, which are discussed in this review. We also discuss the results of recent studies that have reported the novel functions of this polymorphism. Because many BDNF polymorphisms and non-genetic factors have been implicated in the complex traits of neuropsychiatric diseases, the conventional genetic association-based method is limited to address these complex interactions. Future studies should apply data mining and machine learning techniques to determine the genetic role of BDNF in neuropsychiatric diseases.
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Affiliation(s)
- Shih-Jen Tsai
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
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33
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Kitzlerová E, Fišar Z, Lelková P, Jirák R, Zvěřová M, Hroudová J, Manukyan A, Martásek P, Raboch J. Interactions Among Polymorphisms of Susceptibility Loci for Alzheimer's Disease or Depressive Disorder. Med Sci Monit 2018; 24:2599-2619. [PMID: 29703883 PMCID: PMC5944403 DOI: 10.12659/msm.907202] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background Several genetic susceptibility loci for major depressive disorder (MDD) or Alzheimer’s disease (AD) have been described. Interactions among polymorphisms are thought to explain the differences between low- and high-risk groups. We tested for the contribution of interactions between multiple functional polymorphisms in the risk of MDD or AD. Material/Methods A genetic association case-control study was performed in 68 MDD cases, 84 AD cases (35 of them with comorbid depression), and 90 controls. The contribution of 7 polymorphisms from 5 genes (APOE, HSPA1A, SLC6A4, HTR2A, and BDNF) related to risk of MDD or AD development was analyzed. Results Significant associations were found between MDD and interactions among polymorphisms in HSPA1A, SLC6A4, and BDNF or HSPA1A, BDNF, and APOE genes. For polymorphisms in the APOE gene in AD, significant differences were confirmed on the distributions of alleles and genotype rates compared to the control or MDD. Increased probability of comorbid depression was found in patients with AD who do not carry the ɛ4 allele of APOE. Conclusions Assessment of the interactions among polymorphisms of susceptibility loci in both MDD and AD confirmed a synergistic effect of genetic factors influencing inflammatory, serotonergic, and neurotrophic pathways at these heterogenous complex diseases. The effect of interactions was greater in MDD than in AD. A presence of the ɛ4 allele was confirmed as a genetic susceptibility factor in AD. Our findings indicate a role of APOE genotype in onset of comorbid depression in a subgroup of patients with AD who are not carriers of the APOE ɛ4 allele.
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Affiliation(s)
- Eva Kitzlerová
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Zdeněk Fišar
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Petra Lelková
- Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Roman Jirák
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Martina Zvěřová
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Jana Hroudová
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Ada Manukyan
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Pavel Martásek
- Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Jiří Raboch
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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Pfaffenseller B, Kapczinski F, Gallitano AL, Klamt F. EGR3 Immediate Early Gene and the Brain-Derived Neurotrophic Factor in Bipolar Disorder. Front Behav Neurosci 2018; 12:15. [PMID: 29459824 PMCID: PMC5807664 DOI: 10.3389/fnbeh.2018.00015] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 01/17/2018] [Indexed: 01/09/2023] Open
Abstract
Bipolar disorder (BD) is a severe psychiatric illness with a consistent genetic influence, involving complex interactions between numerous genes and environmental factors. Immediate early genes (IEGs) are activated in the brain in response to environmental stimuli, such as stress. The potential to translate environmental stimuli into long-term changes in brain has led to increased interest in a potential role for these genes influencing risk for psychiatric disorders. Our recent finding using network-based approach has shown that the regulatory unit of early growth response gene 3 (EGR3) of IEGs family was robustly repressed in postmortem prefrontal cortex of BD patients. As a central transcription factor, EGR3 regulates an array of target genes that mediate critical neurobiological processes such as synaptic plasticity, memory and cognition. Considering that EGR3 expression is induced by brain-derived neurotrophic factor (BDNF) that has been consistently related to BD pathophysiology, we suggest a link between BDNF and EGR3 and their potential role in BD. A growing body of data from our group and others has shown that peripheral BDNF levels are reduced during mood episodes and also with illness progression. In this same vein, BDNF has been proposed as an important growth factor in the impaired cellular resilience related to BD. Taken together with the fact that EGR3 regulates the expression of the neurotrophin receptor p75NTR and may also indirectly induce BDNF expression, here we propose a feed-forward gene regulatory network involving EGR3 and BDNF and its potential role in BD.
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Affiliation(s)
- Bianca Pfaffenseller
- Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Flavio Kapczinski
- Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, Canada
| | - Amelia L Gallitano
- Department of Basic Medical Sciences, College of Medicine, University of Arizona, Phoenix, AZ, United States
| | - Fábio Klamt
- Laboratory of Cellular Biochemistry, Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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35
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Forebrain-specific ablation of phospholipase Cγ1 causes manic-like behavior. Mol Psychiatry 2017; 22:1473-1482. [PMID: 28138157 DOI: 10.1038/mp.2016.261] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 10/20/2016] [Accepted: 12/06/2016] [Indexed: 02/06/2023]
Abstract
Manic episodes are one of the major diagnostic symptoms in a spectrum of neuropsychiatric disorders that include schizophrenia, obsessive-compulsive disorder and bipolar disorder (BD). Despite a possible association between BD and the gene encoding phospholipase Cγ1 (PLCG1), its etiological basis remains unclear. Here, we report that mice lacking phospholipase Cγ1 (PLCγ1) in the forebrain (Plcg1f/f; CaMKII) exhibit hyperactivity, decreased anxiety-like behavior, reduced depressive-related behavior, hyperhedonia, hyperphagia, impaired learning and memory and exaggerated startle responses. Inhibitory transmission in hippocampal pyramidal neurons and striatal dopamine receptor D1-expressing neurons of Plcg1-deficient mice was significantly reduced. The decrease in inhibitory transmission is likely due to a reduced number of γ-aminobutyric acid (GABA)-ergic boutons, which may result from impaired localization and/or stabilization of postsynaptic CaMKII (Ca2+/calmodulin-dependent protein kinase II) at inhibitory synapses. Moreover, mutant mice display impaired brain-derived neurotrophic factor-tropomyosin receptor kinase B-dependent synaptic plasticity in the hippocampus, which could account for deficits of spatial memory. Lithium and valproate, the drugs presently used to treat mania associated with BD, rescued the hyperactive phenotypes of Plcg1f/f; CaMKII mice. These findings provide evidence that PLCγ1 is critical for synaptic function and plasticity and that the loss of PLCγ1 from the forebrain results in manic-like behavior.
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36
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Park CH, Kim J, Namgung E, Lee DW, Kim GH, Kim M, Kim N, Kim TD, Kim S, Lyoo IK, Yoon S. The BDNF Val66Met Polymorphism Affects the Vulnerability of the Brain Structural Network. Front Hum Neurosci 2017; 11:400. [PMID: 28824404 PMCID: PMC5541016 DOI: 10.3389/fnhum.2017.00400] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 07/19/2017] [Indexed: 12/22/2022] Open
Abstract
Val66Met, a naturally occurring polymorphism in the human brain-derived neurotrophic factor (BDNF) gene resulting in a valine (Val) to methionine (Met) substitution at codon 66, plays an important role in neuroplasticity. While the effect of the BDNF Val66Met polymorphism on local brain structures has previously been examined, its impact on the configuration of the graph-based white matter structural networks is yet to be investigated. In the current study, we assessed the effect of the BDNF polymorphism on the network properties and robustness of the graph-based white matter structural networks. Graph theory was employed to investigate the structural connectivity derived from white matter tractography in two groups, Val homozygotes (n = 18) and Met-allele carriers (n = 55). Although there were no differences in the global network measures including global efficiency, local efficiency, and modularity between the two genotype groups, we found the effect of the BDNF Val66Met polymorphism on the robustness properties of the white matter structural networks. Specifically, the white matter structural networks of the Met-allele carrier group showed higher vulnerability to targeted removal of central nodes as compared with those of the Val homozygote group. These findings suggest that the central role of the BDNF Val66Met polymorphism in regards to neuroplasticity may be associated with inherent differences in the robustness of the white matter structural network according to the genetic variants. Furthermore, greater susceptibility to brain disorders in Met-allele carriers may be understood as being due to their limited stability in white matter structural connectivity.
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Affiliation(s)
- Chang-Hyun Park
- Department of Psychiatry, Catholic University of Korea College of MedicineSeoul, South Korea
| | - Jungyoon Kim
- Ewha Brain Institute, Ewha Womans UniversitySeoul, South Korea.,Department of Brain and Cognitive Sciences, Ewha Womans UniversitySeoul, South Korea
| | - Eun Namgung
- Ewha Brain Institute, Ewha Womans UniversitySeoul, South Korea.,Department of Brain and Cognitive Sciences, Ewha Womans UniversitySeoul, South Korea
| | - Do-Wan Lee
- Ewha Brain Institute, Ewha Womans UniversitySeoul, South Korea
| | - Geon Ha Kim
- Ewha Brain Institute, Ewha Womans UniversitySeoul, South Korea.,Department of Neurology, School of Medicine, Ewha Womans UniversitySeoul, South Korea
| | - Myeongju Kim
- Ewha Brain Institute, Ewha Womans UniversitySeoul, South Korea.,Department of Brain and Cognitive Sciences, Ewha Womans UniversitySeoul, South Korea
| | - Nayeon Kim
- Ewha Brain Institute, Ewha Womans UniversitySeoul, South Korea.,Department of Brain and Cognitive Sciences, Ewha Womans UniversitySeoul, South Korea
| | - Tammy D Kim
- Ewha Brain Institute, Ewha Womans UniversitySeoul, South Korea
| | - Seunghee Kim
- Ewha Brain Institute, Ewha Womans UniversitySeoul, South Korea.,Department of Brain and Cognitive Sciences, Ewha Womans UniversitySeoul, South Korea
| | - In Kyoon Lyoo
- Ewha Brain Institute, Ewha Womans UniversitySeoul, South Korea.,Department of Brain and Cognitive Sciences, Ewha Womans UniversitySeoul, South Korea.,Graduate School of Pharmaceutical Sciences, Ewha Womans UniversitySeoul, South Korea
| | - Sujung Yoon
- Ewha Brain Institute, Ewha Womans UniversitySeoul, South Korea.,Department of Brain and Cognitive Sciences, Ewha Womans UniversitySeoul, South Korea
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Coskunoglu A, Orenay-Boyacioglu S, Deveci A, Bayam M, Onur E, Onan A, Cam FS. Evidence of associations between brain-derived neurotrophic factor (BDNF) serum levels and gene polymorphisms with tinnitus. Noise Health 2017; 19:140-148. [PMID: 28615544 PMCID: PMC5501024 DOI: 10.4103/nah.nah_74_16] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Brain-derived neurotrophic factor (BDNF) gene polymorphisms are associated with abnormalities in regulation of BDNF secretion. Studies also linked BDNF polymorphisms with changes in brainstem auditory-evoked response test results. Furthermore, BDNF levels are reduced in tinnitus, psychiatric disorders, depression, dysthymic disorder that may be associated with stress, conversion disorder, and suicide attempts due to crises of life. For this purpose, we investigated whether there is any role of BDNF changes in the pathophysiology of tinnitus. MATERIALS AND METHODS In this study, we examined the possible effects of BDNF variants in individuals diagnosed with tinnitus for more than 3 months. Fifty-two tinnitus subjects between the ages of 18 and 55, and 42 years healthy control subjects in the same age group, who were free of any otorhinolaryngology and systemic disease, were selected for examination. The intensity of tinnitus and depression was measured using the tinnitus handicap inventory, and the differential diagnosis of psychiatric diagnoses made using the Structured Clinical Interview for Fourth Edition of Mental Disorders. BDNF gene polymorphism was analyzed in the genomic deoxyribonucleic acid (DNA) samples extracted from the venous blood, and the serum levels of BDNF were measured. One-way analysis of variance and Chi-squared tests were applied. RESULTS Serum BDNF level was found lower in the tinnitus patients than controls, and it appeared that there is no correlation between BDNF gene polymorphism and tinnitus. CONCLUSIONS This study suggests neurotrophic factors such as BDNF may have a role in tinnitus etiology. Future studies with larger sample size may be required to further confirm our results.
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Affiliation(s)
- Aysun Coskunoglu
- Department of Medical Genetics, Faculty of Medicine, Celal Bayar University, Manisa, Turkey
| | - Seda Orenay-Boyacioglu
- Department of Medical Genetics, Faculty of Medicine, Adnan Menderes University, Efeler, Aydin, Turkey
| | - Artuner Deveci
- Department of Psychiatry, Faculty of Medicine, Celal Bayar University, Manisa, Turkey
| | - Mustafa Bayam
- Department of Otorhinolaryngology, Faculty of Medicine, Celal Bayar University, Manisa, Turkey
| | - Ece Onur
- Department of Medical Biochemistry, Faculty of Medicine, Celal Bayar University, Manisa, Turkey
| | - Arzu Onan
- Department of Medical Biochemistry, Faculty of Medicine, Celal Bayar University, Manisa, Turkey
| | - Fethi S. Cam
- Department of Medical Genetics, Faculty of Medicine, Celal Bayar University, Manisa, Turkey
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38
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A genetic variant brain-derived neurotrophic factor (BDNF) polymorphism interacts with hostile parenting to predict error-related brain activity and thereby risk for internalizing disorders in children. Dev Psychopathol 2017; 30:125-141. [PMID: 28427482 DOI: 10.1017/s0954579417000517] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The error-related negativity (ERN) is a negative deflection in the event-related potential occurring when individuals make mistakes, and is increased in children with internalizing psychopathology. We recently found that harsh parenting predicts a larger ERN in children, and recent work has suggested that variation in the brain-derived neurotrophic factor (BDNF) gene may moderate the impact of early life adversity. Parents and children completed measures of parenting when children were 3 years old (N = 201); 3 years later, the ERN was measured and diagnostic interviews as well as dimensional symptom measures were completed. We found that harsh parenting predicted an increased ERN only among children with a methionine allele of the BDNF genotype, and evidence of moderated mediation: the ERN mediated the relationship between parenting and internalizing diagnoses and dimensional symptoms only if children had a methionine allele. We tested this model with externalizing disorders, and found that harsh parenting predicted externalizing outcomes, but the ERN did not mediate this association. These findings suggest that harsh parenting predicts both externalizing and internalizing outcomes in children; however, this occurs through different pathways that uniquely implicate error-related brain activity in the development of internalizing disorders.
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39
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Sneha P, Thirumal Kumar D, Saini S, Kajal K, Magesh R, Siva R, George Priya Doss C. Analyzing the Effect of V66M Mutation in BDNF in Causing Mood Disorders: A Computational Approach. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2017; 108:85-103. [PMID: 28427565 DOI: 10.1016/bs.apcsb.2017.01.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Mental disorders or mood disorders are prevalent globally irrespective of region, race, and ethnic groups. Of the types of mood disorders, major depressive disorder (MDD) and bipolar disorder (BPD) are the most prevalent forms of psychiatric condition. A number of preclinical studies emphasize the essential role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of mood disorders. Additionally, BDNF is the most common growth factor in the central nervous system along with their essential role during the neural development and the synaptic elasticity. A malfunctioning of this protein is associated with many types of mood disorders. The variant methionine replaces valine at 66th position is strongly related to BPD, and an individual with a homozygous condition of this allele is at a greater risk of developing MDD. There are very sparse reports suggesting the structural changes of the protein occurring upon the mutation. Consequently, in this study, we applied a computational pipeline to understand the effects caused by the mutation on the protein's structure and function. With the use of in silico tools and computational macroscopic methods, we identified a decrease in the alpha-helix nature, and an overall increase in the random coils that could have probably resulted in deformation of the protein.
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Affiliation(s)
- P Sneha
- School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India
| | - D Thirumal Kumar
- School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India
| | - Sugandhi Saini
- School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India
| | - Kreeti Kajal
- School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India
| | - R Magesh
- Faculty of Research and Bio Medical Sciences, Sri Ramachandra University, Chennai, Tamil Nadu, India
| | - R Siva
- School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India.
| | - C George Priya Doss
- School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India.
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40
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Mitre M, Mariga A, Chao MV. Neurotrophin signalling: novel insights into mechanisms and pathophysiology. Clin Sci (Lond) 2017; 131:13-23. [PMID: 27908981 PMCID: PMC5295469 DOI: 10.1042/cs20160044] [Citation(s) in RCA: 184] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 07/18/2016] [Accepted: 08/09/2016] [Indexed: 12/29/2022]
Abstract
Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are prominent regulators of neuronal survival, growth and differentiation during development. While trophic factors are viewed as well-understood but not innovative molecules, there are many lines of evidence indicating that BDNF plays an important role in the pathophysiology of many neurodegenerative disorders, depression, anxiety and other psychiatric disorders. In particular, lower levels of BDNF are associated with the aetiology of Alzheimer's and Huntington's diseases. A major challenge is to explain how neurotrophins are able to induce plasticity, improve learning and memory and prevent age-dependent cognitive decline through receptor signalling. This article will review the mechanism of action of neurotrophins and how BDNF/tropomyosin receptor kinase B (TrkB) receptor signaling can dictate trophic responses and change brain plasticity through activity-dependent stimulation. Alternative approaches for modulating BDNF/TrkB signalling to deliver relevant clinical outcomes in neurodegenerative and neuropsychiatric disorders will also be described.
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Affiliation(s)
- Mariela Mitre
- Neuroscience and Physiology and Psychiatry, New York University School of Medicine, New York, NY 10016, U.S.A.
- Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, U.S.A
| | - Abigail Mariga
- Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, U.S.A
- Departments of Cell Biology, New York University School of Medicine, New York, NY 10016, U.S.A
| | - Moses V Chao
- Neuroscience and Physiology and Psychiatry, New York University School of Medicine, New York, NY 10016, U.S.A
- Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, U.S.A
- Departments of Cell Biology, New York University School of Medicine, New York, NY 10016, U.S.A
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de Castro-Catala M, van Nierop M, Barrantes-Vidal N, Cristóbal-Narváez P, Sheinbaum T, Kwapil TR, Peña E, Jacobs N, Derom C, Thiery E, van Os J, van Winkel R, Rosa A. Childhood trauma, BDNF Val66Met and subclinical psychotic experiences. Attempt at replication in two independent samples. J Psychiatr Res 2016; 83:121-129. [PMID: 27596955 DOI: 10.1016/j.jpsychires.2016.08.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 08/19/2016] [Accepted: 08/19/2016] [Indexed: 02/06/2023]
Abstract
Childhood trauma exposure is a robust environmental risk factor for psychosis. However, not all exposed individuals develop psychotic symptoms later in life. The Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) has been suggested to moderate the psychosis-inducing effects of childhood trauma in clinical and nonclinical samples. Our study aimed to explore the interaction effect between childhood trauma and the BDNF Val66Met polymorphism on subclinical psychotic experiences (PEs). This was explored in two nonclinical independent samples: an undergraduate and technical-training school student sample (n = 808, sample 1) and a female twin sample (n = 621, sample 2). Results showed that childhood trauma was strongly associated with positive and negative PEs in nonclinical individuals. A BDNF Val66Met x childhood trauma effect on positive PEs was observed in both samples. These results were discordant in terms of risk allele: while in sample 1 Val allele carriers, especially males, were more vulnerable to the effects of childhood trauma regarding PEs, in sample 2 Met carriers presented higher PEs scores when exposed to childhood trauma, compared with Val carriers. Moreover, in sample 2, a significant interaction was also found in relation to negative PEs. Our study partially replicates previous findings and suggests that some individuals are more prone to develop PEs following childhood trauma because of a complex combination of multiple factors. Further studies including genetic, environmental and epigenetic factors may provide insights in this field.
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Affiliation(s)
- Marta de Castro-Catala
- Secció de Zoologia i Antropologia Biològica, Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain
| | - Martine van Nierop
- KU Leuven, Department of Neuroscience, Research Group Psychiatry, Centre for Contextual Psychiatry, Leuven, Belgium
| | - Neus Barrantes-Vidal
- Departament de Psicologia Clínica i de la Salut, Facultat de Psicologia, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain; Department of Psychology, University of North Carolina at Greensboro, Greensboro, NC, United States; Sant Pere Claver - Fundació Sanitària, Barcelona, Spain; Centre for Biomedical Research Network on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
| | - Paula Cristóbal-Narváez
- Departament de Psicologia Clínica i de la Salut, Facultat de Psicologia, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain
| | - Tamara Sheinbaum
- Departament de Psicologia Clínica i de la Salut, Facultat de Psicologia, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain
| | - Thomas R Kwapil
- Department of Psychology, University of North Carolina at Greensboro, Greensboro, NC, United States
| | - Elionora Peña
- Secció de Zoologia i Antropologia Biològica, Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain
| | - Nele Jacobs
- KU Leuven, Department of Neuroscience, Research Group Psychiatry, Centre for Contextual Psychiatry, Leuven, Belgium; Faculty of Psychology, Open University of the Netherlands, Heerlen, The Netherlands
| | - Catherine Derom
- Centre of Human Genetics, University Hospital Leuven, Department of Human Genetics, Leuven, Belgium
| | - Evert Thiery
- Department of Neurology, Ghent University Hospital, Ghent, Belgium
| | - Jim van Os
- Department of Psychosis Studies, Institute of Psychiatry, King's College London, King's Health Partners, London, United Kingdom; Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht, The Netherlands
| | - Ruud van Winkel
- KU Leuven, Department of Neuroscience, Research Group Psychiatry, Centre for Contextual Psychiatry, Leuven, Belgium; University Psychiatric Center, Katholieke Universiteit Leuven, Belgium
| | - Araceli Rosa
- Secció de Zoologia i Antropologia Biològica, Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Centre for Biomedical Research Network on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
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42
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Li M, Chang H, Xiao X. BDNF Val66Met polymorphism and bipolar disorder in European populations: A risk association in case-control, family-based and GWAS studies. Neurosci Biobehav Rev 2016; 68:218-233. [DOI: 10.1016/j.neubiorev.2016.05.031] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 05/11/2016] [Accepted: 05/24/2016] [Indexed: 01/15/2023]
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43
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Plant N. Can a systems approach produce a better understanding of mood disorders? Biochim Biophys Acta Gen Subj 2016; 1861:3335-3344. [PMID: 27565355 DOI: 10.1016/j.bbagen.2016.08.016] [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: 02/17/2016] [Revised: 07/29/2016] [Accepted: 08/22/2016] [Indexed: 10/21/2022]
Abstract
BACKGROUND One in twenty-five people suffer from a mood disorder. Current treatments are sub-optimal with poor patient response and uncertain modes-of-action. There is thus a need to better understand underlying mechanisms that determine mood, and how these go wrong in affective disorders. Systems biology approaches have yielded important biological discoveries for other complex diseases such as cancer, and their potential in affective disorders will be reviewed. SCOPE OF REVIEW This review will provide a general background to affective disorders, plus an outline of experimental and computational systems biology. The current application of these approaches in understanding affective disorders will be considered, and future recommendations made. MAJOR CONCLUSIONS Experimental systems biology has been applied to the study of affective disorders, especially at the genome and transcriptomic levels. However, data generation has been slowed by a lack of human tissue or suitable animal models. At present, computational systems biology has only be applied to understanding affective disorders on a few occasions. These studies provide sufficient novel biological insight to motivate further use of computational biology in this field. GENERAL SIGNIFICANCE In common with many complex diseases much time and money has been spent on the generation of large-scale experimental datasets. The next step is to use the emerging computational approaches, predominantly developed in the field of oncology, to leverage the most biological insight from these datasets. This will lead to the critical breakthroughs required for more effective diagnosis, stratification and treatment of affective disorders.
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Affiliation(s)
- Nick Plant
- School of Bioscience and Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7XH, UK.
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Castrén E, Kojima M. Brain-derived neurotrophic factor in mood disorders and antidepressant treatments. Neurobiol Dis 2016; 97:119-126. [PMID: 27425886 DOI: 10.1016/j.nbd.2016.07.010] [Citation(s) in RCA: 245] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 06/21/2016] [Accepted: 07/13/2016] [Indexed: 12/12/2022] Open
Abstract
Levels of brain-derived neurotrophic factor (BDNF) are reduced in the brain and serum of depressed patients and at least the reduction in serum levels is reversible upon successful treatment. These data, together with a wealth of reports using different animal models with depression-like behavior or manipulation of expression of BDNF or its receptor TrkB have implicated BDNF in the pathophysiology of depression as well as in the mechanism of action of antidepressant treatments. Recent findings have shown that posttranslational processing of BDNF gene product can yield different molecular entities that differently influence signaling through BNDF receptor TrkB and the pan-neurotrophin receptor p75NTR. We will here review these data and discuss new insights into the possible pathophysiological roles of those new BDNF subtypes as well as recent findings on the role of BDNF mediated neuronal plasticity in mood disorders and their treatments.
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Affiliation(s)
- Eero Castrén
- Neuroscience Center, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland.
| | - Masami Kojima
- Biomedical Research Institute, Advanced Industrial Science and Technology (AIST), Osaka 563-8577, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan.
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Cao B, Bauer IE, Sharma AN, Mwangi B, Frazier T, Lavagnino L, Zunta-Soares GB, Walss-Bass C, Glahn DC, Kapczinski F, Nielsen DA, Soares JC. Reduced hippocampus volume and memory performance in bipolar disorder patients carrying the BDNF val66met met allele. J Affect Disord 2016; 198:198-205. [PMID: 27018938 PMCID: PMC5214589 DOI: 10.1016/j.jad.2016.03.044] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 03/08/2016] [Accepted: 03/09/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Previous studies investigated the impact of brain-derived neurotrophic factor (BDNF) val66met (rs6265) on hippocampus volumes and neurocognition in bipolar disorders (BD), but the results were not consistent. This study aimed to investigate the effect of BDNF polymorphism on hippocampus volumes and memory performance in well-characterized adult populations diagnosed with type I BD (BD-I) and major depressive disorder (MDD) compared with healthy controls (HC). METHODS 48 BD-I patients, 33 MDD patients and 60 HC were genotyped for BDNF rs6265 using DNA isolated from white blood cells. Individuals with val/met and met/met genotypes were grouped as met carriers and compared to those with the val/val. Brain segmentations were obtained from structural magnetic resonance imaging (MRI) using the Freesurfer. Memory performance was assessed with the California Verbal Learning Task (CVLT). RESULTS We found a significant diagnosis effect and marginal interaction between diagnosis and BDNF genotype group for both hippocampus volumes and memory performance. BDNF met allele carrier BD patients had smaller hippocampus volumes and reduced performance on multiple CVLT scores compared to MDD patients and HC. CONCLUSIONS We provide strong evidence for the BDNF val66met polymorphism as a putative biological signature for the neuroanatomical and cognitive abnormalities commonly observed in BD patients.
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Affiliation(s)
- Bo Cao
- Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, United States.
| | | | | | - Benson Mwangi
- Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Thomas Frazier
- The Center for Pediatric Behavioral Health and Center for Autism, Cleveland Clinic, Cleveland, OH, United States
| | - Luca Lavagnino
- Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Giovana B. Zunta-Soares
- Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Consuelo Walss-Bass
- Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - David C. Glahn
- The Olin Neuropsychiatry Research Center, Institute of Living, and Department of Psychiatry, Yale University School of Medicine, CT, United States
| | - Flavio Kapczinski
- Department of Psychiatry, Universidade Federal Rio Grande do Sul, Rua Ramiro Barcelos, 2350, 90035-903, Rio Grande do Sul, Brazil
| | - David A. Nielsen
- Department of Psychiatry and Behavioral Sciences, Michael E. DeBakey V.A. Medical Center, Baylor College of Medicine, Houston, TX, United States
| | - Jair C. Soares
- Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, United States
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Naaldijk YM, Bittencourt MC, Sack U, Ulrich H. Kinins and microglial responses in bipolar disorder: a neuroinflammation hypothesis. Biol Chem 2016; 397:283-96. [DOI: 10.1515/hsz-2015-0257] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 02/04/2016] [Indexed: 12/27/2022]
Abstract
Abstract
Bipolar disorder (BD) is a severe psychiatric disorder that affects up to 15% of the worldwide population. Characterized by switches in mood between mania and depression, its etiology is still unknown and efforts have been made to elucidate the mechanisms involved in first episode, development and progression of the disorder. Microglia activation, abnormal activity of GSK-3β and reduction in neurotrophic factor expression related to neuroinflammatory processes have been indicated to be part of the disorder’s pathophysiology. Lithium, the main mood stabilizer used for the treatment and prevention of relapses, acts as an anti-inflammatory agent. Based on that, here we suggest a neuroinflammatory pathway for would be BD progression, in which microglia activation states modulated via constitutive induction of kinin-B1 receptor and reduction of kinin-B2 receptor expression and activity.
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Zhang L, Li XX, Hu XZ. Post-traumatic stress disorder risk and brain-derived neurotrophic factor Val66Met. World J Psychiatry 2016; 6:1-6. [PMID: 27014593 PMCID: PMC4804258 DOI: 10.5498/wjp.v6.i1.1] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 10/23/2015] [Accepted: 12/21/2015] [Indexed: 02/05/2023] Open
Abstract
Brain-derived neurotrophic factor (BDNF), which regulates neuronal survival, growth differentiation, and synapse formation, is known to be associated with depression and post-traumatic stress disorder (PTSD). However, the molecular mechanism for those mental disorders remains unknown. Studies have shown that BDNF is associated with PTSD risk and exaggerated startle reaction (a major arousal manifestation of PTSD) in United States military service members who were deployed during the wars in Iraq and Afghanistan. The frequency of the Met/Met in BDNF gene was greater among those with PTSD than those without PTSD. Among individuals who experienced fewer lifetime stressful events, the Met carriers have significantly higher total and startle scores on the PTSD Checklist than the Val/Val carriers. In addition, subjects with PTSD showed higher levels of BDNF in their peripheral blood plasma than the non-probable-PTSD controls. Increased BDNF levels and startle response were observed in both blood plasma and brain hippocampus by inescapable tail shock in rats. In this paper, we reviewed these data to discuss BDNF as a potential biomarker for PTSD risk and its possible roles in the onset of PTSD.
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Zanardini R, Ciani M, Benussi L, Ghidoni R. Molecular Pathways Bridging Frontotemporal Lobar Degeneration and Psychiatric Disorders. Front Aging Neurosci 2016; 8:10. [PMID: 26869919 PMCID: PMC4740789 DOI: 10.3389/fnagi.2016.00010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 01/12/2016] [Indexed: 12/12/2022] Open
Abstract
The overlap of symptoms between neurodegenerative and psychiatric diseases has been reported. Neuropsychiatric alterations are commonly observed in dementia, especially in the behavioral variant of frontotemporal dementia (bvFTD), which is the most common clinical FTD subtype. At the same time, psychiatric disorders, like schizophrenia (SCZ), can display symptoms of dementia, including features of frontal dysfunction with relative sparing of memory. In the present review, we discuss common molecular features in these pathologies with a special focus on FTD. Molecules like Brain Derived Neurotrophic Factor (BDNF) and progranulin are linked to the pathophysiology of both neurodegenerative and psychiatric diseases. In these brain-associated illnesses, the presence of disease-associated variants in BDNF and progranulin (GRN) genes cause a reduction of circulating proteins levels, through alterations in proteins expression or secretion. For these reasons, we believe that prevention and therapy of psychiatric and neurological disorders could be achieved enhancing both BDNF and progranulin levels thanks to drug discovery efforts.
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Affiliation(s)
- Roberta Zanardini
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli Brescia, Italy
| | - Miriam Ciani
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli Brescia, Italy
| | - Luisa Benussi
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli Brescia, Italy
| | - Roberta Ghidoni
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli Brescia, Italy
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Morales-Marín ME, Genis-Mendoza AD, Tovilla-Zarate CA, Lanzagorta N, Escamilla M, Nicolini H. Association between obesity and the brain-derived neurotrophic factor gene polymorphism Val66Met in individuals with bipolar disorder in Mexican population. Neuropsychiatr Dis Treat 2016; 12:1843-8. [PMID: 27524902 PMCID: PMC4966648 DOI: 10.2147/ndt.s104654] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The brain-derived neurotrophic factor (BDNF) has been considered as an important candidate gene in bipolar disorder (BD); this association has been derived from several genetic and genome-wide studies. A polymorphic variant of the BDNF (Val66Met) confers some differences in the clinical presentation of affective disorders. In this study, we evaluated a sample population from Mexico City to determine whether the BDNF (rs6265) Val66Met polymorphism is associated with the body mass index (BMI) of patients with BD. METHODS This association study included a sample population of 357 individuals recruited in Mexico City. A total of 139 participants were diagnosed with BD and 137 were classified as psychiatrically healthy controls (all individuals were interviewed and evaluated by the Diagnostic Interview for Genetic Studies). Genomic DNA was extracted from peripheral blood leukocytes. The quantitative polymerase chain reaction (qPCR) assay was performed in 96-well plates using the TaqMan Universal Thermal Cycling Protocol. After the PCR end point was reached, fluorescence intensity was measured in a 7,500 real-time PCR system and evaluated using the SDS v2.1 software, results were analyzed with Finetti and SPSS software. Concerning BMI stratification, random groups were defined as follows: normal <25 kg/m(2), overweight (Ow) =25.1-29.9 kg/m(2), and obesity (Ob) >30 kg/m(2). RESULTS In the present work, we report the association of a particular BMI phenotype with the presence of the Val66Met allele in patients with BD (P=0.0033 and odds ratio [95% confidence interval] =0.332 [157-0.703]), and correlated the risk for valine allele carriers with Ow and Ob in patients with BD. CONCLUSION We found that the methionine allele confers a lower risk of developing Ow and Ob in patients with BD. We also confirmed that the G polymorphism represents a risk of developing Ow and Ob in patients with BD. In future studies, the haplotype analysis should provide additional evidence that BDNF may be associated with BD and BMI within the Mexican population.
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Affiliation(s)
- Mirna Edith Morales-Marín
- Genomics of Psychiatric and Neurodegenerative Diseases Laboratory, National Institute of Genomic Medicine (INMEGEN), CDMX, Mexico
| | - Alma Delia Genis-Mendoza
- Genomics of Psychiatric and Neurodegenerative Diseases Laboratory, National Institute of Genomic Medicine (INMEGEN), CDMX, Mexico; Psychiatric Care Services, Child Psychiatric Hospital Dr Juan N Navarro, CDMX, Mexico
| | | | | | - Michael Escamilla
- Department of Psychiatry, Paul L Foster School of Medicine, Texas Tech University Health Science Center, El Paso TX, USA
| | - Humberto Nicolini
- Genomics of Psychiatric and Neurodegenerative Diseases Laboratory, National Institute of Genomic Medicine (INMEGEN), CDMX, Mexico; Carracci Medical Group, CDMX, Mexico
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Yang YR, Kang DS, Lee C, Seok H, Follo MY, Cocco L, Suh PG. Primary phospholipase C and brain disorders. Adv Biol Regul 2015; 61:80-5. [PMID: 26639088 DOI: 10.1016/j.jbior.2015.11.003] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 11/17/2015] [Accepted: 11/17/2015] [Indexed: 11/19/2022]
Abstract
In the brain, the primary phospholipase C (PLC) proteins, PLCβ, and PLCγ, are activated primarily by neurotransmitters, neurotrophic factors, and hormones through G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). Among the primary PLC isozymes, PLCβ1, PLCβ4, and PLCγ1 are highly expressed and differentially distributed, suggesting a specific role for each PLC subtype in different regions of the brain. Primary PLCs control neuronal activity, which is important for synapse function and development. In addition, dysregulation of primary PLC signaling is linked to several brain disorders including epilepsy, schizophrenia, bipolar disorder, Huntington's disease, depression and Alzheimer's disease. In this review, we included current knowledge regarding the roles of primary PLC isozymes in brain disorders.
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Affiliation(s)
- Yong Ryoul Yang
- Center for Cell to Cell Communication in Cancers (C5), School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, 689-798, Republic of Korea
| | - Du-Seock Kang
- Center for Cell to Cell Communication in Cancers (C5), School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, 689-798, Republic of Korea
| | - Cheol Lee
- Center for Cell to Cell Communication in Cancers (C5), School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, 689-798, Republic of Korea
| | - Heon Seok
- Department of Biomedical Engineering, Jungwon University, Goesan, Chungcheongbukdo, Republic of Korea
| | - Matilde Y Follo
- Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Lucio Cocco
- Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Pann-Ghill Suh
- Center for Cell to Cell Communication in Cancers (C5), School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, 689-798, Republic of Korea.
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