Simvastatin attenuation of cerebral vasospasm after subarachnoid hemorrhage in rats via increased phosphorylation of Akt and endothelial nitric oxide synthase

Abstract

The mechanisms involved in simvastatin-mediated attenuation of cerebral vasospasm after subarachnoid hemorrhage (SAH) are unclear. We investigated the role of the phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway and endothelial nitric oxide synthase (eNOS) in the cerebral vasculature in statin-mediated attenuation of cerebral vasospasm using wortmannin, an irreversible pharmacological PI3K inhibitor, and a rat SAH endovascular perforation model. Simvastatin was administered intraperitoneally in two dosages (1 mg/kg and 20 mg/kg) at 0.5, 24, and 48 hr after SAH and histological parameters of ipsilateral intracranial carotid artery (ICA) were assessed at 24 and 72 hr. SAH significantly decreased ICA diameter and perimeter while increasing wall thickness at both 24 and 72 hr. High-dosage simvastatin prevented the reduction of ICA diameter and perimeter following SAH, whereas both high and low dosages reduced wall thickness significantly at 24 and 72 hr. The effects of simvastatin were significantly reversed by wortmannin. High-dosage simvastatin increased pAkt and peNOS (phosphorylated forms) levels without increasing Akt and eNOS expression compared with the SAH group and also improved neurological deficits at 24 and 72 hr. Simvastatin did not affect protein levels by itself compared with untreated sham group. The present study elucidates the critical role of the PI3K activation leading to phosphorylation of Akt and eNOS in simvastatin-mediated attenuation of cerebral vasospasm after SAH.

Age-Dependent Rescue by Simvastatin of Alzheimer's Disease Cerebrovascular and Memory Deficits

“…Although not measured in the current study, myogenic tone of cerebral arteries is also highly sensitive to ROS (Maneen and Cipolla, 2007), and simvastatin may have acted at this level. Yet, an activating effect of simvastatin on brain endothelial NOS activity (Sugawara et al, 2008) and a direct relaxant effect through KCa channel activation, as reported for rosuvastatin in peripheral arteries (Ló pez et al, 2008), could also contribute to the functional recovery.…”

Nitric Oxide in Early Brain Injury After Subarachnoid Hemorrhage

“…eNOS decrease will create a local NO deficiency in the cerebral vessels promoting constriction and adhesion of platelet and leukocytes to the endothelium [1,55]. It is also interesting to note that animals that are either pretreated or given multiple statins (increases eNOS protein expression) treatment extending from phase I to III develop little delayed vasospasm after SAH [56,57]. That, this observation could not be repeated in clinical SAH may represent delay in initiation of this therapy due to reasons mentioned above [58,59].…”

Increased ICP promotes CaMKII-mediated phosphorylation of neuronal NOS at Ser847 in the hippocampus immediately after subarachnoid hemorrhage

“…NOtargeted therapies for cerebral vasospasm have been intensively studied. Simvastatin has been shown to increase eNOS activity via the phosphatidylinositol 3-kinase/Akt pathway and to attenuate cerebral vasospasm (McGirt et al, 2002;Sugawara et al, 2008). Moreover, decreased NO availability, which plays an important role in acute cerebral vasoconstriction and ischemic brain damage, has been observed during the acute stage of SAH Sehba et al, 1999Sehba et al, , 2000.…”