Assessment of the effect of the nitric oxide synthase inhibitors on DNA methylation and the activity and expression of DNA methyltransferases in rat brain cell culture.

• Grant number: 15/25067-6
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: March 01, 2016
• End date: February 28, 2017
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Sâmia Regiane Lourenço Joca
• Grantee: Izaque de Sousa Maciel
• Supervisor: Eero Castren
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: University of Helsinki, Finland
• Associated to the scholarship: 15/06271-1 - Assessment of the effect of the nitric oxide synthase inhibitors on DNA methylation and the activity and expression of DNA methyltransferase enzymes in rat brain subjected to stress, BP.DR

Abstract

The majority of major depression (MD) is preceded by stressful events. The stress leads to an increase in glutamate release, synthesis and release of nitric oxide (NO) as well as epigenetic changes induced by increased DNA methylation in the promoter regions of genes involved in the pathophysiology of MD. It has been demonstrated that oxidative stress and NO can modulate mediators responsible for the control of DNA methylation in cell culture and that NOS inhibitors increase BDNF expression and TrkB signaling in rat hippocampal. This data suggest a link between NO, neuronal plasticity and epigenetic modulation. So, more studies are necessary to answer this question. However, it not known role of NO in the DNA methylation induced by corticosterone rat brain cell cultures stimulated with corticosterone. The hypothesis of this project is that the increased NO levels in neuronal cell treated with corticosterone, change the activity and/or expression of DNMTs enzymes (DNA methyltransferases) and accordingly DNA methylation in the promoter regions of genes linked behavioral stress and the neurobiology of depression. For this, neuronal cell culture will be challenge with corticosterone and treated with inhibitors of nNOS (7-NI) or iNOS (aminoguanidine). Will be evaluated the NO levels and cell viability front of the pharmacological treatments, as well as the role of NO and NOS inhibitors on the methylation of genes (BDNF and TrkB), and the expression of these proteins, as well as activity and DNMTs expression in cell culture. The results of this study may contribute to the advancement about the intracellular signaling of mechanisms involved in the neurobiology of DM, enabling the identification of new biological targets of therapeutic interest in the treatment of DM.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MACIEL, IZAQUE DE SOUSA; SALES, AMANDA J.; CASAROTTO, PLINIO C.; CASTREN, EERO; BIOJONE, CAROLINE; JOCA, SAMIA R. L.. Nitric Oxide Synthase inhibition counteracts the stress-induced DNA methyltransferase 3b expression in the hippocampus of rats. European Journal of Neuroscience, DEC 2020. (15/25067-6, 15/06271-1, 17/24304-0)

MACIEL, IZAQUE DE SOUSA; SALES, AMANDA J.; CASAROTTO, PLINIO C.; CASTREN, EERO; BIOJONE, CAROLINE; JOCA, SAMIA R. L.. Nitric Oxide Synthase inhibition counteracts the stress-induced DNA methyltransferase 3b expression in the hippocampus of rats. European Journal of Neuroscience, v. 55, n. 9-10, p. 14-pg., 2020-12-06. (15/25067-6, 15/06271-1, 17/24304-0)

MACIEL, I.; SALES, A. J.; JOCA, S. R. L.. Treatment with nitric oxide synthesis inhibitors decreases global DNA methylation in the ventral hippocampus of rats submitted to learned helplessness. European Neuropsychopharmacology, v. 26, p. 1-pg., 2016-10-01. (15/25067-6, 15/06271-1)