Nitric Oxide Synthase inhibition counteracts the stress-induced DNA methyltransferase 3b expression in the hippocampus of rats

Author(s)

Maciel, Izaque de Sousa ^[1] ; Sales, Amanda J. ^[1] ; Casarotto, Plinio C. ^[2] ; Castren, Eero ^[2] ; Biojone, Caroline ^[2] ; Joca, Samia R. L. ^{[3, 4]}

Affiliation

^[1] Univ Sao Paulo, Sch Med Ribeirao Preto, Ribeirao Preto, SP - Brazil

^[2] Univ Helsinki, HiLIFE, Neurosci Ctr, Haartmaninkatu 8, Helsinki - Finland

^[3] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Biomol Sci, Ribeirao Preto, SP - Brazil

^[4] Aarhus Univ, Dept Biomed, Translat Neuropsychiat Unit, Dept Clin Med, Aarhus - Denmark

• Document type: Journal article
• Source: European Journal of Neuroscience; DEC 2020.
• Web of Science Citations: 0

Abstract

It has been postulated that the activation of NMDA receptors (NMDAr) and nitric oxide (NO) production in the hippocampus is involved in the behavioral consequences of stress. Stress triggers NMDAr-induced calcium influx in limbic areas, such as the hippocampus, which in turn activates neuronal NO synthase (nNOS). Inhibition of nNOS or NMDAr activity can prevent stress-induced effects in animal models, but the molecular mechanisms behind this effect are still unclear. In this study, cultured hippocampal neurons treated with NMDA or dexamethasone showed an increased of DNA methyltransferase 3b (DNMT3b) mRNA expression, which was blocked by pre-treatment with nNOS inhibitor n(omega)-propyl-l-arginine (NPA). In rats submitted to the Learned Helplessness paradigm (LH), we observed that inescapable stress increased DNMT3b mRNA expression at 1h and 24h in the hippocampus. The NOS inhibitors 7-NI and aminoguanidine (AMG) decreased the number of escape failures in LH and counteracted the changes in hippocampal DNMT3b mRNA induced in this behavioral paradigm. Altogether, our data suggest that NO produced in response to NMDAr activation following stress upregulates DNMT3b in the hippocampus. (AU)

• FAPESP's process: 15/25067-6 - 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.
• Grantee: Izaque de Sousa Maciel
• Support type: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 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
• Grantee: Izaque de Sousa Maciel
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/24304-0 - New perspectives in the use of drugs that modify atypical neurotransmitters in the treatment of neuropsychiatric disorders
• Grantee: Francisco Silveira Guimaraes
• Support type: Research Projects - Thematic Grants