title: Inhibition of histone deacetylation protects wildtype but not gelsolin-deficient mice from ischemic brain injury.
abstract: Acetylation/deactylation of histones is an important mechanism to regulate gene expression and chromatin remodeling. We have previously demonstrated that the HDAC inhibitor trichostatin A (TSA) protects cortical neurons from oxygen/glucose deprivation in vitro which is mediated--at least in part--via the up regulation of gelsolin expression. Here, we demonstrate that TSA treatment dose-dependently enhances histone acetylation in brains of wildtype mice as evidenced by immunoblots of total brain lysates and immunocytochemical staining. Along with increased histone acetylation dose-dependent up regulation of gelsolin protein was observed. Levels of filamentous actin were largely decreased by TSA pre-treatment in brain of wildtype but not gelsolin-deficient mice. When exposed to 1 h filamentous occlusion of the middle cerebral artery followed by reperfusion TSA pre-treated wildtype mice developed significantly smaller cerebral lesion volumes and tended to have improved neurological deficit scores compared to vehicle-treated mice. These protective effects could not be explained by apparent changes in physiological parameters. In contrast to wildtype mice, TSA pre-treatment did not protect gelsolin-deficient mice against MCAo/reperfusion suggesting that enhanced gelsolin expression is an important mechanism by which TSA protects against ischemic brain injury. Our results suggest that HDAC inhibitors such as TSA are a promising therapeutic strategy for reducing brain injury following cerebral ischemia.
authors.affiliation: Klinik und Poliklinik für Neurologie, Charité-Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, D-10117 Berlin, Germany.
authors.forename: Ferah
authors.initials: F
authors.lastname: Yildirim
authors.forename: Karen
authors.initials: K
authors.lastname: Gertz
authors.forename: Golo
authors.initials: G
authors.lastname: Kronenberg
authors.forename: Christoph
authors.initials: C
authors.lastname: Harms
authors.forename: Klaus B
authors.initials: KB
authors.lastname: Fink
authors.forename: Andreas
authors.initials: A
authors.lastname: Meisel
authors.forename: Matthias
authors.initials: M
authors.lastname: Endres
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001930:Brain Injuries / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002545:Brain Ischemia / Q000150:complications* / Q000188:drug therapy; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D018260:Gelsolin / Q000172:deficiency*; D005947:Glucose / Q000172:deficiency; D006657:Histones / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000627:therapeutic use; D000860:Hypoxia; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D018260:Gelsolin; D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A; D010751:Phosphopyruvate Hydratase; D005947:Glucose; D002118:Calcium