Simvastatin activates Akt/glycogen synthase kinase-3beta 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/GSK3beta 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-GSK3beta 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-GSK3beta, 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 microg/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/GSK3beta survival signal and inhibition of caspase-dependent apoptosis pathway.
Cheng
Gao
G
Department of Neurosurgery, The First affiliated hospital of Harbin Medical University, No.23, Youzheng Street, Nangang District, Harbin, China. doctorgaocheng@yahoo.com.cn
Chunlei
Wang
W
Pei
Wu
W
Zhen
Liu
L
Xiangzhen
Liu
L
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology
D061945:Caspase Inhibitors; D019821:Simvastatin; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3