HDAC5 y SIRT2, dos dianas farmacológicas implicadas en el fenotipo depresivo y en la acción antidepresiva

Abstract

Depression is a chronic disabling disorder mainly characterized by anhedonia and depressed mood, and still unresolved in terms of aetiology and response to treatment. Growing evidence suggests that epigenetic mechanisms play a key role in neuronal plasticity, and, therefore, mediate stable functional changes in the brain in response to environmental stimuli. Specifically, stress-mediated epigenetic changes in limbic regions that can persist for a lifetime, could contribute to the pathogenesis of depression. Likewise, antidepressant therapy might be achieved in part via epigenetic mechanisms. Moreover, epigenetic modifications could establish the basis for the interindividual variability in vulnerability to adversity and/or response to treatment. It was observed that chronic stress induced epigenetic changes in histone remodelling affecting expression of genes involved in neural plasticity. Specifically, two histone deacetylases, Hdac5 and Sirt2, which were oppositely regulated by stress and antidepressant drug in the prefrontal cortex of mice, were identified. These enzymes could contribute to stable stress-induced neuronal adaptations. In addition, repeated reboxetine treatment increased the phosphorylated form of HDAC5 (P-HDAC5), indicating that noradrenaline mediates cytoplasmic export of this enzyme. Moreover, SIRT2 was downregulated by all monoaminergic antidepressants (fluoxetine, reboxetine and imipramine) suggesting that these effects could contribute to the well-known beneficial effects of antidepressants on brain plasticity. Finally, correlating with what it happens with antidepressant treatment, repeated treatment with specific Hdacs inhibitors for three weeks increased synaptic plasticity in the prefrontal cortex. Moreover, using the compound 33i, reported as a selective SIRT2 inhibitor in vitro, it was shown that SIRT2 inhibition modulates glutamate and serotonin systems in the mouse prefrontal cortex and induced an antidepressant-like action. It is highlighted the therapeutic potential of SIRT2 as a new pharmacological target for the treatment of major depression and the need to further investigate the role of SIRT2 inhibitors as antidepressant agents. In summary, this study supports the hypothesis that associates major depression and antidepressant therapy with epigenetic changes that may explain the large inter-individual variability of response to adversity or treatment.