The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) Confers Acute Neuroprotection After Intracerebral Hemorrhage in Mice.
Spontaneous intracerebral hemorrhage (ICH) is a stroke subtype with no effective treatment. Though ICH is known to induce severe neurological damage, the molecular mechanisms of neurological injury after ICH remain largely unclear. Given the emerging role of epigenetic mechanisms in neurodegeneration, the present study evaluated whether suberoylanilide hydroxamic acid (SAHA: vorinostat), a clinically well-tolerated pan-histone deacetylase inhibitor (HDACi), would attenuate neurological injury and improve functional outcomes in a preclinical model of ICH. Mice were administered with SAHA or vehicle after an induction of ICH and acute neuronal death, glial activation, and neurological outcomes were assessed. SAHA-treated mice exhibited less neurodegeneration with concomitant improvement in neurological outcomes than vehicle-treated mice. Furthermore, SAHA downregulated glial activation and the expression of heme oxygenase-1, a stress-inducible enzyme that plays critical roles in neurological damage after ICH. Altogether, the data strongly suggest the role of epigenetic mechanisms in inducing neurological injury after ICH and raise the possible clinical utility of SAHA for therapeutic intervention after ICH.
Department of Neurosurgery, Georgia Regents University, 1120 15th Street CA1010, Augusta, GA, 30912, USA. sramesh@gru.edu.
Sangeetha
S
Sukumari-Ramesh
Department of Neurosurgery, Georgia Regents University, 1120 15th Street CA1010, Augusta, GA, 30912, USA.
Cargill H
CH
Alleyne
Department of Neurosurgery, Georgia Regents University, 1120 15th Street CA1010, Augusta, GA, 30912, USA.
Krishnan M
KM
Dhandapani
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001930:Brain Injuries / Q000209:etiology / Q000517:prevention & control*; D002543:Cerebral Hemorrhage / Q000150:complications* / Q000188:drug therapy*; D004195:Disease Models, Animal; D005452:Fluoresceins / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009460:Neurologic Examination; D000077337:Vorinostat
D005452:Fluoresceins; D005904:Glial Fibrillary Acidic Protein; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008565:Membrane Proteins; C435731:fluoro jade; D000077337:Vorinostat; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
Gliosis; Microglial activation; Stroke