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

VILLARREAL A; CIERI MB; RAMOS AJ

Congreso; Reunion Anual de la Sociedad Argentina de Investigación Clínica; 2018

Brain stroke is still of major concern in medicine and the lack of effi- cient treatments is because of the incompletely understood molec- ular mechanisms underlying neuronal death. A key factor promoting neurodegeneration is the reactive astrogliosis (RA) in which astro- cytes drastically change morphology, become pro-inflammatory and form the glial scar blocking axonal regeneration. This phenotype fol- lows changes in the programs of gene expression and we showed that activation of transcription factor NFkB is at least one of the pathways responsible for the phenomenon. We aim now to address what happens at the chromatin level in terms of gene regulation by epigenetic mechanisms. We analyzed astrocytic response in vivo using a model of brain ischemia by cortical devascularization and in vitro by exposing primary cultures of astrocytes to ischemic con- ditions. 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 inhib- itor of histones deacetylases. At 14DPL the glial scar is formed and astrocyte reactivity is confined only to the region around the isch- emic core in control animals. Surprisingly, in VPA injected animals we observed expansion of the damage and immunofluorescence for GFAP and Vimentin showed that astrocytes were highly more reac- tive. We observed in these animals a higher cell infiltration. Histone 3 acetylation (H3ac) levels in inmunoblot indicated that this mark decreases immediately after ischemia and then increases compared to control. Confocal microscopy revealed a very heterogeneous pat- tern of H3ac in nuclei from reactive astrocytes. Our results suggest that astrocytes suffer epigenetic modifications in response to brain ischemia and that these changes may be instrumental for the proper evolution of the process of RA. We consider that understanding this mechanism is of high relevance for designing new therapeutic strat- egies which aim to modulate gliosis and inflammation. PICT2015- 1451/UBACYT.