Neuroprotective Effects of Selective Inhibition of Histone Deacetylase 3 in Experimental Stroke

AbstractHistone deacetylase 3 (HDAC3) has been implicated as neurotoxic in several neurodegenerative conditions. However, the role of HDAC3 in ischemic stroke has not been thoroughly explored. We tested the hypothesis that selective inhibition of HDAC3 after stroke affords neuroprotection. Adult male Wistar rats (n = 8/group) were subjected to 2 h of middle cerebral artery occlusion (MCAO), and randomly selected animals were treated intraperitoneally twice with either vehicle (1% Tween 80) or a selective HDAC3 inhibitor (RGFP966, 10 mg/kg) at 2 and 24 h after MCAO. Long-term behavioral tests were perfo rmed up to 28 days after MCAO. Another set of rats (n = 7/group) were sacrificed at 3 days for histological analysis. Immunostaining for HDAC3, acetyl-Histone 3 (AcH3), NeuN, TNF-alpha, toll-like receptor 4 (TLR4), cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP), Akt, and TUNEL were performed. Selective HDAC3 inhibition improved lo ng-term functional outcome (p <  0.05) and reduced infarct volume (p <  0.0001). HDAC3 inhibition increased levels of AcH3 in the ischemic brain (p = 0.016). Higher levels of AcH3 were significantly correlated with better neurological scores and smaller infarct volumes (r = 0.74,p = 0.002;r = 0.6,p = 0.02, respectively). The RGFP966 treatment reduced apoptosis—TUNEL+, cleaved caspase-3+, and cleaved PARP+ cells—and neuroinflammation—TNF-alpha+ and TLR4+ cells—in the ischemic border...
Source: Translational Stroke Research - Category: Neurology Source Type: research