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Effect of inhibitors of DNMTs and antidepressants on DNA methylation in candidate genes involved in the neurobiology of depression

Grant number: 15/01955-0
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): January 01, 2016
Effective date (End): March 31, 2018
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Sâmia Regiane Lourenço Joca
Grantee:Amanda Juliana Sales
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Introduction: Epigenetic mechanisms, such as DNA methylation (is regulated by DNMTs), are thought to play an important role in the neurobiology of depression. In this sense, we demonstrated that inhibitors DNA methylation have antidepressant-like effect in animals submitted to forced swimming test and tail suspension. Objectives: Whereas DNMTs inhibitors have different mechanism of action the conventional antidepressants, this study will test the hypothesis that these drugs induce the same behavioral effect but acute and long term. In addition, we will evaluate if the stress would be able to induce change in the mRNA and DNA methylation levels in different genes associated with depression and regulated by epigenetic mechanisms (BDNF, TrkB, 5-HT1A, NMDA, AMPA) in different brain structures (dorsal and ventral hippocampus, and prefrontal cortex) and whether these changes were attenuated by treatment with acute administration of DNMTs inhibitors and chronis adinistration of antidepressants. Methods: Rats will be submitted to the inescapable shocks (IC) or habituation (Hab) and will receive systemic injection of DNMTs inhibitors, 5-Azad (0.1, 0.2 and 0.4 mg / kg; n=10-12/group) and RG108 (0.2, 0.4 and 0.6 mg / kg; n=10-12/group), antidepressants, imipramine (15 mg / kg; n=10-12/group) or fluoxetine (20 mg / kg; n=10-12/group) or vehicle for 1 (acute group) or 7 days (chronic group) and submitted to the learned helplessness test on the last day. Additionally, a group will be submitted only to the pre-test and will receive the treatments, and the last injection will be administered 1 hour before sacrifice (n=10-12/group). The animals will be anesthetized, decapitated and dissected the brain structures for RNA and methylated DNA isolation for subsequent quantification by real time qPCR.

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)
SALES, AMANDA J.; FOGACA, MANOELA V.; SARTIM, ARIANDRA G.; PEREIRA, VITOR S.; WEGENER, GREGERS; GUIMARAES, FRANCISCO S.; JOCA, SAMIA R. L. Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex. Molecular Neurobiology, v. 56, n. 2, p. 1070-1081, FEB 2019. Web of Science Citations: 17.
SALES, AMANDA J.; CRESTANI, CARLOS C.; GUIMARAES, FRANCISCO S.; JOCA, SAMIA R. L. Antidepressant-like effect induced by Cannabidiol is dependent on brain serotonin levels. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 86, p. 255-261, AUG 30 2018. Web of Science Citations: 11.
SARTIM, ARIANDRA G.; SALES, AMANDA J.; GUIMARAES, FRANCISCO S.; JOCA, SAMIA R. L. Hippocampal mammalian target of rapamycin is implicated in stress-coping behavior induced by cannabidiol in the forced swim test. JOURNAL OF PSYCHOPHARMACOLOGY, v. 32, n. 8, p. 922-931, AUG 2018. Web of Science Citations: 3.

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