Simvastatin attenuates cerebral vasospasm and improves outcomes by upregulation of PI3K/Akt pathway in a rat model of subarachnoid hemorrhage.
BACKGROUND
Cerebral vasospasm is a common sequelae of subarachonoid hemorrhage (SAH), however, the mechanism of cerebral vasospasm is still unclear. Recently, statins have been shown to have efficacy in ameliorating cerebral vasospasm. The present study investigates whether simvastatin attenuates cerebral vasospasm after subarachnoid hemorrhage (SAH) via upregulation of the PI3K/Akt pathway.


METHODS
47 adult male Sprague-Dawley rats were divided into 6 groups: sham-operated, SAH treated with vehicle, SAH treated with low dose simvastatin (1 mg/kg), high dose simvastatin (20 mg/kg), SAH treated with simvastatin plus the PI3K inhibitor (wortmannin), and sham-operated plus wortmannin. Simvastatin was administered intraperitoneally 30 minutes after SAH created by the standard endovascular perforation model. Histological parameters of the ipsilateral internal carotid artery (ICA-diameter, perimeter, and wall thickness) and neurological score were assessed at 24 hours.


RESULTS
Mortality was reduced to zero in both the treated groups as compared to 20% in the vehicle-treated and 36% in the simvastatin plus wortmannin-treated groups. The decrease in ICA diameter and perimeter observed in vehicle-treated group (203.2 +/- 10.3 microm, 652.7 +/- 29.0 microm) as compared to sham (259.7 +/- 10.6, 865.4 +/- 39.5) were significantly attenuated by high-dose simvastatin (267.4 +/- 8.0, 882.4 +/- 30.0). The increase in wall thickness (vehicle 29.50 +/- 2.42 microm v/s sham 9.52 +/- 0.56 microm) was significantly attenuated by both high and low dose simvastatin (11.87 +/- 1.56, 19.75 +/- 1.40). These effects of simvastatin were blocked with the addition of wortmannin (162.7 +/- 20.6, 528.9 +/- 65.9, 29.19 +/- 1.97). High dose simvastatin improved the neurological deficits after SAH, but this was also blocked by wortmannin.


CONCLUSIONS
The beneficial effects of high dose simvastatin in ameliorating cerebral vasospasm are likely mediated by upregulation of the PI3K/Akt pathway.
Sugawara
Takashi
T
Department of Physiology, Loma Linda University, 11041 Campus Street, RH214, Loma Linda, CA 92350, USA. sugataka@nifty.com
Jadhav
Vikram
V
Ayer
Robert
R
Zhang
John
J
D000704:Analysis of Variance; D000818:Animals; D002343:Carotid Artery, Internal / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000627:therapeutic use*; D013345:Subarachnoid Hemorrhage / Q000150:complications; D015854:Up-Regulation / Q000187:drug effects*; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D051057:Proto-Oncogene Proteins c-akt