Suppression of the Rho/Rho-Kinase Pathway and Prevention of Cerebral Vasospasm by Combination Treatment with Statin and Fasudil After Subarachnoid Hemorrhage in Rabbit

Abstract

The Rho/Rho-kinase pathway is considered important in the pathogenesis of sustained smooth muscle cell contraction during cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). The aims of this study were to investigate whether combination treatment, with pitavastatin as an inhibitor of RhoA and fasudil as an inhibitor of Rho-kinase, prevents the cerebral vasospasm. SAH was simulated using the double-hemorrhage rabbit model, and pitavastatin, or fasudil, or both (combination treatment) were administrated. The basilar artery (BA) cross-sectional area only in the combination treatment group was statistically larger than in the SAH group (p<0.05). BA Rhokinase, as measured by ELISA, was statistically reduced only in the combination treatment group compared with the SAH group (p<0.05). In the other two treatment groups, pitavastatin or fasudil treatment group showed larger BA cross-sectional areas and lower value for BA Rho-kinase, but there were no statistically significant differences compared with the SAH group. The expression of endothelial nitric oxide synthase (eNOS), evaluated by immunohistochemistry in the pitavastatin group and the combination group, was higher than in the SAH group. Results indicate that combination treatment could extensively prevent cerebral vasospasm due to the synergic effect of combining pitavastatin and fasudil on the Rho/Rho-kinase pathway and on eNOS.

Controversies and evolving new mechanisms in subarachnoid hemorrhage

“…The Rho/Rho-kinase pathway is the main regulator of these actin-dependent cell functions in the pathogenesis of sustained smooth muscle cell contraction and vasospasm (Satoh et al, 2012; Takai et al, 1995). Therefore, the combination of treatment with an inhibitor of RhoA, pitavastatin, and an inhibitor of Rho-kinase, fasudil, could extensively prevent cerebral vasospasm after SAH (Naraoka et al, 2013). Furthermore, phosphorylations trigger SAH-induced vasculopathy in cerebral arteries, as determined by quantitative mass spectrometry, including focal adhesion complexes, ERK1/2, calcium calmodulin-dependent kinase II, STAT3, and c-Jun (Parker et al, 2013).…”

Drug treatment of cerebral vasospasm after subarachnoid hemorrhage following aneurysms

“…It was suggested that hydroxyfasudil was contributed to the potency of fasudil to prevent CVS and hyperviscosity, and the potential utility of hydroxyfasudil as a therapeutic agent for patients with SAH was also suggested. However, Naraoka M et al [28] employed the double-hemorrhage rabbit model to investigate whether the combination treatment, consisting of pitavastatin as an inhibitor of RhoA and fasudil as an inhibitor of Rho-kinase, prevented CVS. And the results showed the cross-sectional area of basilar artery were significantly increased only by the combination treatment, and the separate use of fasudil or pitavastatin had no significant effect.…”

Nitric oxide-mediated inhibition of phenylephrine-induced contraction in response to hypothermia is partially modulated by endothelial Rho-kinase

“…The cholesterollowering drugs known as statins inhibit 3-hydroxy-3methylglutaryl-coenzyme A, thereby inhibiting the synthesis of isoprenoids (geranyl-geranyl pyrophosphate) and cholesterol, leading to inhibition of Rho-kinase and increased NO production [11]. Combined treatment with the Rho-kinase inhibitor fasudil and statins prevents cerebral spasm after subarachnoid hemorrhage [12]. However, exposure to cold temperatures causes vessels to constrict via a mechanism involving reactive oxygen speciesinduced activation of Rho-kinase, alpha-2 adrenoceptor translocation and decreased NO production [13].…”