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

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

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

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

Nucleocytoplasmic export of HDAC5 and SIRT2 downregulation: two epigenetic mechanisms by which antidepressants enhance synaptic plasticity markers

Rationale: Antidepressant action has been linked to increased synaptic plasticity in which epigenetic mechanisms such as histone posttranslational acetylation could be involved. Interestingly, the histone deacetylases HDAC5 and SIRT2 are oppositely regulated by stress and antidepressants in mice prefrontal cortex (PFC). Besides, the neuroblastoma SH-SY5Y line is an in vitro neuronal model reliable to study drug effects with clear advantages over animals. Objectives: We aimed to characterize in vitro the role of HDAC5 and SIRT2 in antidepressant regulation of neuroplasticity. Methods: SH-SY5Y cultures were incubated with imipramine, fluoxetine, and reboxetine (10 μM, 2 and 24 h) as well as the selective HDAC5 (MC3822, 5 μM, 24 h) or SIRT2 (33i, 5 μM, 24 h) inhibitors. The regulation of the brain-derived neurotrophic factor (BDNF), the vesicular glutamate transporter 1 (VGLUT1), the acetylated histones 3 (AcH3) and 4 (AcH4), HDAC5, and SIRT2 was studied. Comparatively, the long-term effects of these antidepressants (21 days, i.p.) in the mice (C57BL6, 8 weeks) PFC were studied. Results: Antidepressants increased both in vitro and in vivo expression of BDNF, VGLUT1, AcH3, and AcH4. Moreover, imipramine and reboxetine increased the phosphorylated form of HDAC5 (P-HDAC5), mediating its cytoplasmic export. Further, SIRT2 was downregulated by all antidepressants. Finally, specific inhibition of HDAC5 and SIRT2 increased neuroplasticity markers. Conclusions: This study supports the validity of the SH-SY5Y model for studying epigenetic changes linked to synaptic plasticity induced by antidepressants as well as the effect of selective HDAC inhibitors. Particularly, nucleocytoplasmic export of HDAC5 and SIRT2 downregulation mediated by antidepressants could enhance synaptic plasticity markers leading to antidepressant action

Chronic stress and antidepressant induced changes in Hdac5 and Sirt2 affect synaptic plasticity

Changes in histone acetylation could contribute to the pathogenesis of depression and antidepressant therapy. Using the chronic social defeat stress (CSDS) model of depression and different antidepressant treatments we studied the regulation of histone deacetylases (Hdac׳s) and synaptic plasticity markers in the prefrontal cortex (PFC). Further, functional implication of identified Hdac׳s in brain plasticity was explored. Mice were exposed to CSDS (10 days) followed by saline or imipramine (4 weeks). PFC Hdac׳s mRNA abundance was studied and compared to human׳s. Further, protein expression of acetylated histones (AcH3 and AcH4), neuroplasticity markers (CREB and pro-BDNF) and selected Hdac׳s were analyzed. Moreover, other antidepressants (fluoxetine and reboxetine) and selective HDAC inhibitors were studied. CSDS increased Hdac5 and Sirt2 mRNA whereas repeated imipramine did the opposite. Accordingly, stress and imipramine induced opposite changes on AcH3, AcH4 and CREB expression. At protein level, CSDS upregulated nuclear fraction of Hdac5 and repeated imipramine and reboxetine increased its phosphorylated form (p-Hdac5), mainly located in the cytoplasm. Moreover, Sirt2 was downregulated by all monoaminergic antidepressants. Further, repeated treatment with the class IIa Hdac inhibitor MC1568 and the Sirt2 inhibitor 33i for three weeks increased synaptic plasticity in the prefrontal cortex. Our results suggest that Hdac5 and Sirt2 upregulation could constitute stable stress-induced neuronal adaptations. Noteworthy, the SIRT2 upregulation in depressed patients supports the interest of this target for therapeutic intervention. On the other hand, cytoplasmic Hdac5 export and Sirt2 downregulation induced by monoaminergic antidepressants could contribute to the well-known beneficial effects of antidepressants on brain plasticity

Datos preliminares sobre la variación en caracteres relacionados con la productividad y la calidad en distintos biotipos de Garnacha Blanca

La Garnacha Blanca es una variedad de creciente interés en varias regiones vitícolas del valle del Ebro. En la Comunidad de Navarra, se está llevando a cabo un proceso de selección clonal sobre una colección de biotipos navarros de esta variedad. Con el fin de apoyar la toma de decisiones en este proceso, estamos analizando la variación existente para caracteres de interés de calidad y productividad en dicha colección y en esta comunicación se presentan los trabajos realizados y los datos obtenidos durante el primer año de análisis. Para este estudio se ha considerado un biotipo procedente de cada parcela original en base a los datos preliminares de caracterización agronómica y enológica de todos los biotipos recopilados. En relación con la productividad se han analizado la viabilidad del polen, la tasa de cuajado, el número de semillas, el tamaño de las bayas, el índice de millerandage y de corrimiento y el tamaño de los racimos. Relacionado con la calidad se ha realizado un estudio detallado de la compacidad del racimo. Esta fue valorada de manera visual según el descriptor OIV 204 y también se midieron diversos caracteres morfológicos con el objetivo de estudiar su posible relación con el descriptor de compacidad. Los datos preliminares muestran una tendencia general, según la cual los racimos más compactos se corresponden con los de mayor tamaño, con mayor tasa de cuajado y también tienen las bayas más grandes, existiendo una gradación hacia los racimos más sueltos, de menor tamaño, con bayas más pequeñas y menor tasa de cuajado. Por otro lado, se han identificado dos biotipos que no siguen este patrón general, y presentan los tamaños mayores de racimo y de baya, aun cuando su compacidad es media

Datos preliminares sobre la variación en caracteres relacionados con la productividad y la calidad en distintos biotipos de Garnacha Blanca

Trabajo presentado a las II Jornadas del Grupo de Viticultura y Enología (SECH), celebradas en Madrid el 3 y 4 de noviembre de 2016.La Garnacha Blanca es una variedad de creciente interés en varias regiones vitícolas del valle del Ebro. En la Comunidad de Navarra, se está llevando a cabo un proceso de selección clonal sobre una colección de biotipos navarros de esta variedad. Con el fin de apoyar la toma de decisiones en este proceso, estamos analizando la variación existente para caracteres de interés de calidad y productividad en dicha colección y en esta comunicación se presentan los trabajos realizados y los datos obtenidos durante el primer año de análisis. Para este estudio se ha considerado un biotipo procedente de cada parcela original en base a los datos preliminares de caracterización agronómica y enológica de todos los biotipos recopilados. En relación con la productividad se han analizado la viabilidad del polen, la tasa de cuajado, el número de semillas, el tamaño de las bayas, el índice de millerandage y de corrimiento y el tamaño de los racimos. Relacionado con la calidad se ha realizado un estudio detallado de la compacidad del racimo. Esta fue valorada de manera visual según el descriptor OIV204 y también se midieron diversos caracteres morfológicos con el objetivo de estudiar su posible relación con el descriptor de compacidad. Los datos preliminares muestran una tendencia general, según la cual los racimos más compactos se corresponden con los de mayor tamaño, con mayor tasa de cuajado y también tienen las bayas más grandes, existiendo una gradación hacia los racimos más sueltos, de menor tamaño, con bayas más pequeñas y menor tasa de cuajado. Por otro lado, se han identificado dos biotipos que no siguen este patrón general, y presentan los tamaños mayores de racimo y de baya, aun cuando su compacidad es media.Peer Reviewe