Involvement of BDNF-TrkB-mTOR pathway of the ventral medial prefrontal cortex in antidepressant-like effect induced by inhibitors of DNA methylation.

• Grant number: 12/05750-5
• Support Opportunities: Scholarships in Brazil - Master
• Start date: July 01, 2012
• End date: March 31, 2014
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Sâmia Regiane Lourenço Joca
• Grantee: Angélica Caroline Dutra Romano
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Recently suspected that epigenetic mechanisms could be related to the pathophysiology of depression have been raised. Recent studies indicate that changes in gene transcription induced by stress or antidepressant drugs appear to involve epigenetic mechanisms. For example, DNA methylation, which is associated with transcriptional repression is increased by exposure to stress, and high levels of methylation at loci were found in specific brain suicide. In this sense, preliminary results of our research group indicated pioneered global inhibition of DNA methylation by systemic administration of an inhibitor of DNA methyltransferase (DNMTs), 5-aza-2-deoxycytidine induces antidepressant-like effect dose-dependent in the animal model of forced swimming in rats. However, the molecular mechanisms and the brain structures involved in these effects, as well as the profile of pharmacological effect induced by these treatments have not been investigated. The medial prefrontal cortex ventral (MPFCv) is a limbic structure closely related to the neurobiology of depression. Recent evidence indicates that the antidepressant-like effect appears associated with increased levels of the neurotrophin BDNF (brain derived neurotrophic factor) and its receptor TrkB in CPFMv, and the intracellular signaling mediated by activation of protein m-TOR. However, there is no evidence that these molecular mechanisms are involved in the effects induced by inhibitors of DNA methylation. It is, however, that both the BDNF and TrkB have its expression is regulated by DNA methylation. Therefore, the objective of this study is to investigate the role of BDNF-TrkB Recently suspected that epigenetic mechanisms could be related to the pathophysiology of depression have been raised. Recent studies indicate that changes in gene transcription induced by stress or antidepressant drugs appear to involve epigenetic mechanisms. For example, DNA methylation, which is associated with transcriptional repression is increased by exposure to stress, and high levels of methylation at loci were found in specific brain suicide. In this sense, preliminary results of our research group indicated pioneered global inhibition of DNA methylation by systemic administration of an inhibitor of DNA methyltransferase (DNMTs), 5-aza-2-deoxycytidine induces antidepressant-like effect dose-dependent in the animal model of forced swimming in rats. However, the molecular mechanisms and the brain structures involved in these effects, as well as the profile of pharmacological effect induced by these treatments have not been investigated. The MPFC is a limbic structure closely related to the neurobiology of depression. Recent evidence indicates that the antidepressant-like effect appears associated with increased levels of the neurotrophin BDNF and its receptor TrkB in MPFCv, and the intracellular signaling mediated by activation of protein m-TOR. However, there is no evidence that these molecular mechanisms are involved in the effects induced by inhibitors of DNA methylation. It is, however, that both the BDNF and TrkB have its expression is regulated by DNA methylation. Therefore, the objective of this study is to investigate the role of BDNF-TrkB-mTor pathway in MPFCv in the antidepressant effect induced by inhibitors of DNA methylation. For this, rats treated with inhibitors of DNA methylation are submitted to forced swimming test, and then these animals the MPFCv is dissected for analysis of expression of BDNF, TrkB and m- TOR as well as DNA methylation. In another experiment, separate groups of animals submitted to forced swimming be treated systemically or azad 5-RG-108 and receive intra-MPFCv of K252a or rapamycin in order to investigate the effect of the drugs depends on the BDNF-TrkB-mTOR pathway in CPFMv