Rol de la acetilación y metilación de histonas en una nueva generación de antidepresivos
Dra. María
Dra. María ZorrillaZubilete caracterizadas por separado. Por ejemplo, las modificaciones epigenéticas que ocurren en neuronas glutamatérgicas piramidales en la corteza prefrontal son probablemente muy diferentes de los que ocurren en varios subtipos diferentes de interneuronas GABAérgicas, astrocitos y oligodendrocitos. Afortunadamente, estamos viendo la aparición de herramientas que permiten la investigación específica del tipo celular, de las modificaciones de la cromatina en un tejido heterogéneo como el cerebro (203). Para una comprensión completa de los mecanismos epigenéticos de estrés y la acción antidepresiva, se debe hacer la transición a escala del genoma. Como se señaló anteriormente, la combinación de numerosas modificaciones de la cromatina (204) permitirá el trazado del epigenoma antidepresivo. Estos son solo algunos ejemplos de las nuevas líneas de investigación que potencialmente podrían revelar mecanismos fundamentalmente nuevos que controlen los fenómenos relacionados con el estrés. Por último, ha habido un interés, en las posibles aplicaciones terapéuticas de fármacos dirigidos a enzimas modificadores de la cromatina (211). Por ejemplo, los inhibidores de HDAC que ejercen respuestas de tipo antidepresivo potentes en diversos modelos animales. Si tales fármacos ofrecen posibilidades realistas para el descubrimiento de fármacos sigue siendo incierto, dado que la mayoría de las proteínas de modificación en la cromatina se expresan ampliamente en todo el cerebro y en los tejidos periféricos. Por otra parte, no hay duda de que la caracterización epigenética del estrés por diferentes modelos revelará una visión mucho más completa de la gama de proteínas y ncRNAs que median la patología inducida por el estrés, la reversión de la patología con un tratamiento antidepresivo y el desarrollo de dicha patología en individuos resistentes. Este conocimiento proporcionará por primera vez una guía general para los futuros esfuerzos de descubrimiento de fármacos. Es evidente que la modificación de histonas tiene un rol importante en la patofisiología de la depresión. Dependiendo de la región del cerebro y de la modificación de histonas involucrada se activará o reprimirá la expresión de genes asociados con su patofisiología. La gran expectativa es desarrollar estudios de genoma amplio que contribuyan al desarrollo de nuevos biomarcadores de la enfermedad y de esta forma contribuir a optimizar el tratamiento antidepresivo. Referencias bibliográficas • Andrus BM, Blizinsky K, Vedell PT, Dennis K, Shukla PK, et al. 2012. Gene expression patterns in the hippocampus and amygdala of endogenous depression and chronic stress models. Mol. Psychiatry 17:49–61. • Bale TL, Baram TZ, Brown AS, Goldstein JM, Insel TR, et al. 2010. Early life programming and neurodevelopmental disorders. Biol. Psychiatry 68:314–19. • Barhwal K, et al. (2009) Acetyl-L-carnitine (ALCAR) prevents hypobaric hypoxia-induced spatial memory impairment through extracellular related kinase-mediated nuclear factor erythroid 2-related factor 2 phosphorylation. Neuroscience 161(2):501–514. • Berger SL. 2007. The complex language of chromatin regulation during transcription. Nature 447:407–12. • Berman RM, et al. (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47(4):351–354. • Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, et al. 2006. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311:864–68. • Bird A. 2007. Perceptions of epigenetics. Nature 447:396–98. • Bird A. 2008. The methyl-CpG-binding protein MeCP2 and neurological disease. Biochem. Soc. Trans. 36:575–83. • Chahrour M, Jung SY, ShawC,ZhouX,Wong ST, et al. 2008. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320:1224–29. • Champagne FA, Weaver IC, Diorio J, Dymov S, Szyf M, Meaney MJ. 2006. Maternal care associated with methylation of the estrogen receptor-α1b promoter and estrogen receptor-α expression in the medial preoptic area of female offspring. Endocrinology 147:2909–15. • Champagne FA. 2008. Epigenetic mechanisms and the transgenerational effects of maternal care. Front. Neuroendocrinol. 29:386–97. • Chertkow-Deutsher Y, Cohen H, Klein E, Ben- Shachar D. 2010. DNA methylation in vulnerability to post-traumatic stress in rats: evidence for the role of the post-synaptic density protein Dlgap2. Int. J. Neuropsychopharmacol. 13:347–59. • Cheung P, Allis CD, Sassone-Corsi P. 2000. Signaling to chromatin through histone modifications. Cell 103:263–71. • Christoffel DJ, Golden SA, Russo SJ (2011) Structural and synaptic plasticity in stress-related disorders. Rev Neurosci 22(5):535–549. • Chrousos GP. 2009. Stress and disorders of the stress system. Nat. Rev. Endocrinol. 5:374–81. • Covington HE III, Maze I, LaPlantQ, VialouV,Ohnishi Y, et al. 2009. Antidepressant actions of histone deacetylase inhibitors. J. 26 // EDITORIAL SCIENS
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