INHIBITION OF HISTONE DEACETYLASES AFTER THE ONSET OF BRAIN ISCHEMIA IMPAIRS NORMAL EVOLUTION OF REACTIVE ASTROGLIOSIS AND EXACERBATES THE DAMAGE

VILLARREAL A; CIERI B; RAMOS AJ

Congreso; LXIII Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2018

Sociedad Argentina de Investigación Clínica

Brain stroke is still of major concern in medicine and the lack of efficienttreatments is because of the incompletely understood molecularmechanisms underlying neuronal death. A key factor promotingneurodegeneration is the reactive astrogliosis (RA) in which astrocytesdrastically change morphology, become pro-inflammatory andform the glial scar blocking axonal regeneration. This phenotype followschanges in the programs of gene expression and we showedthat activation of transcription factor NFkB is at least one of thepathways responsible for the phenomenon. We aim now to addresswhat happens at the chromatin level in terms of gene regulation byepigenetic mechanisms. We analyzed astrocytic response in vivousing a model of brain ischemia by cortical devascularization andin vitro by exposing primary cultures of astrocytes to ischemic conditions.At 1/2/3 days post lesion (DPL) animals were injected (i.p.)with a single dose of 300mg/kg/day of valproic acid (VPA), an inhibitorof histones deacetylases. At 14DPL the glial scar is formed andastrocyte reactivity is confined only to the region around the ischemiccore in control animals. Surprisingly, in VPA injected animalswe observed expansion of the damage and immunofluorescence forGFAP and Vimentin showed that astrocytes were highly more reactive.We observed in these animals a higher cell infiltration. Histone3 acetylation (H3ac) levels in inmunoblot indicated that this markdecreases immediately after ischemia and then increases comparedto control. Confocal microscopy revealed a very heterogeneous patternof H3ac in nuclei from reactive astrocytes. Our results suggestthat astrocytes suffer epigenetic modifications in response to brainischemia and that these changes may be instrumental for the properevolution of the process of RA. We consider that understanding thismechanism is of high relevance for designing new therapeutic strategieswhich aim to modulate gliosis and inflammation. PICT2015-1451/UBACYT.