Nitric oxide (NO) is an important cell messenger that plays several pathophysiological functions. In the central nervous system (CNS) this gaseous molecule modulates the release of several neurotransmitters and mediates important effects, such as cell proliferation, LTP and dendritic sprout. Evidence has suggested that the nitrergic signaling imbalance may be associated to the etiology of humor disorders. In animal models, systemic administration of NO inhibitors induces antidepressant-like effects. Nevertheless, our group has recently observed a paradox: iNOS knockout (KO) mice present increased levels of NO in the frontal cortex and antidepressant-like phenotype in the forced swimming test. Preliminary data suggests that restoring the normal levels of NO in the FC (by chronic treatment with NOS inhibitors) attenuates the antidepressant-like phenotype of iNOS KO mice. Despite several studies have reported a dual effect of NO in distinct pathological and physiological conditions, there is insufficient information about the dual role of NO mediating the pro/antidepressant behavior.Moreover, regardless the dual effect of NO in animal models sensitive to antidepressant drugs has been described over a decade, most of studies have focused only in the mechanisms involved in the antidepressant-like effects of NOS inhibitors. Thus, the molecular and cellular mechanisms involved in the antidepressant-like effects associated to elevated levels of NO were not investigated until now. Based on recent evidence from in vitro studies pointing that NO is increases the transcription of CREB-regulated genes (such as BDNF), the aim of present project is investigate the hypothesis that NO facilitates the BDNF-TrkB signaling in FC, through epigenetic mechanisms (nitrosylation of histone deacetylase 2, followed by increased in hitone acetylation and increased binding of CREB to the BDNF promoter), thus inducing antidepressant-like effects.
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