Role of Akt/GSK-3β signaling pathway in trichostatin-A-induced reduction of cerebral ischemia-reperfusion injury in mice

Objective To evaluate the role of protein kinase B/glycogen synthase kinase-3 beta (Akt/GSK-3β) signaling pathway in trichostatin-A (TSA)-induced reduction of cerebral ischemia-reperfusion (I/R) injury in mice. Methods Forty pathogen-free healthy male Balb/c mice, weighing 18-22 g, were divided into 4 groups (n=10 each) using a random number table method: sham operation group (S group), I/R group, TSA group and TSA plus Akt inhibitor LY294002 group (TL group). Cerebral I/R was induced by middle cerebral artery occlusion (1-h ischemia followed by 24-h reperfusion). TSA 5 mg/kg was intraperitoneally injected for 3 consecutive days before establishing the model in TSA group.TSA 5 mg/kg was intraperitoneally injected for 3 consecutive days before establishing the model, and LY294002 15 nmol/kg was injected via the caudal vein at 30 min before establishing the model.Brain tissues were obtained at 24 h of reperfusion for determination of cerebral infarct size (by TTC), activities of superoxide dismutase (SOD) and reactive oxygen species (ROS) and malondialdehyde (MDA) content (by colorimetric assay), cell apoptosis (by TUNEL) and expression of Akt, phosphorylated Akt (p-Akt), GSK-3β and phosphorylated GSK-3β (p-GSK-3β). The apoptosis index and ratios of p-Akt/Akt and p-GSK-3β/GSK-3β were calculated. Results Compared with S group, the cerebral infarct size was significantly increased, the activity of SOD in brain tissues was decreased, the MDA content and ROS activity in brain tissues and apoptosis index were increased, and the ratios of p-Akt/Akt and p-GSK-3β/GSK-3β were decreased in I/R group (P<0.05). Compared with I/R group, the cerebral infarct size was significantly decreased, the activity of SOD in brain tissues was increased, the MDA content and ROS activity in brain tissues and apoptosis index were decreased, and the ratios of p-Akt/Akt and p-GSK-3β/GSK-3β were decreased in TSA group (P<0.05). Compared with TSA group, the cerebral infarct size was significantly increased, the activity of SOD in brain tissues was decreased, the MDA content and ROS activity in brain tissues and apoptosis index were increased, and the ratios of p-Akt/Akt and p-GSK-3β/GSK-3β were decreased in TL group (P<0.05). Conclusion The mechanism by which TSA attenuates cerebral I/R injury is related to activating Akt/GSK-3β signaling pathway in mice. Key words: Histone deacetylase inhibitors; Protein-serine-threonine kinases; Glycogen synthase kinase 3; Brain; Reperfusion injury