Simvastatin activates Akt/glycogen synthase kinase-3β signal and inhibits caspase-3 activation after experimental subarachnoid hemorrhage

This study was designed to explore the role of simvastatin and its effects on the Akt/GSK3β survival signal and apoptosis pathway after experimental subarachnoid hemorrhage (SAH). SAH was induced by blood injection into the cisterna magna in New Zealand white rabbits. Increased expression of phospho-Akt and phospho-GSK3β was observed in brain tissue after SAH. Apoptosis and related proteins, including P53, apoptosis-inducing factor (AIF), cytochrome C, and cleaved caspase-3, were also activated. Simvastatin, at both low dose (10 mg/kg) and high dose (40 mg/kg), further increased expression of phospho-Akt and phospho-GSK3β, decreased activation of caspase-3, and inhibited apoptosis. Preserved blood-brain barrier and attenuated brain edema were observed following simvastatin treatment. In addition, the neuroprotective effects of simvastatin were blocked by wortmannin (2.5 µg/kg/min), an irreversible PIK3 inhibitor. P53, AIF, and cytochrome C were not affected by simvastatin treatment. Findings from the present study suggest that simvastatin ameliorates acute brain injury after SAH. The potential mechanisms of action include activation of the Akt/GSK3β survival signal and inhibition of caspase-dependent apoptosis pathway.

Graphical abstractSimvastatin increased phospho-Akt and phospho-GSK3β expression and inhibited caspase-3 activation, while no significant effects on P53, AIF, and cytochrome-C expression after SAH. (DMSO, referred as SAH model treated with DMSO; W + S, referred as simvastatin plus wortmannin; L + T, referred as low dose simvastatin and H + T referred as high dose simvastatin.)Figure optionsDownload full-size imageDownload as PowerPoint slide