Inhibitory Effects of Eicosapentaenoic Acid on Chronic Cerebral Vasospasm after Subarachnoid Hemorrhage: Possible Involvement of a Sphingosylphosphorylcholine-Rho-Kinase Pathway

Abstract

Background and Purpose: Rho-kinase (ROK)-mediated Ca²⁺ sensitization of vascular smooth muscle (VSM) contraction plays a pivotal role in cerebral vasospasm (CV). We previously demonstrated that sphingosylphosphorylcholine (SPC) induces Ca²⁺ sensitization through sequential activation of the Src family protein tyrosine kinases (Src-PTKs) and ROK in vitro, and that Ca²⁺ sensitization is inhibited by eicosapentaenoic acid (EPA) through the selective inactivation of Src-PTK. In this study, we examined whether SPC induced CV in vivo, and, if it did, whether EPA would inhibit CV, as induced by SPC or in an in vivo model of subarachnoid hemorrhage (SAH). Methods: Changes in the diameter of the canine basilar artery were investigated by angiography after administering SPC into the cisterna magna. Then, Y27632, a specific Rho-kinase inhibitor, or EPA was injected intracisternally and the effects of both agents were investigated. In another experiment using a single-hemorrhage model, Y27632 or EPA was injected on day 7 after SAH and the changes in the diameter of the canine basilar artery were investigated. Results: At cerebrospinal fluid concentrations of 100 and 300 µmol/l, SPC induced severe vasoconstriction (maximum vasoconstriction by SPC (100 µmol/l): 61.8 ± 8.2%), which was markedly reversed by Y27632 (96.3 ± 4.4%) or EPA (92.6 ± 12.8%). SAH caused severe vasospasm on day 7 (67.6 ± 7.8%), which was significantly blocked by Y27632 (95.5 ± 10.6%) or EPA (90.0 ± 4.4%). Conclusions: SPC is a novel mediator of ROK-induced CV in vivo. The inhibition of CV induced by SPC or after SAH by EPA suggests beneficial roles of EPA in the treatment of CV. Our findings are compatible with the notion that the SPC-ROK pathway may be involved in CV.

Rho/Rho-Associated Coiled-Coil Forming Kinase Pathway as Therapeutic Targets for Statins in Atherosclerosis

“…ROCK inhibitors, such as fasudil have been shown to prevent cerebral vasospasm after subarachnoid hemorrhage (160,166). Similarly, animal studies showed that fasudil and Y-27632 could inhibit the development of atherosclerosis and arterial remodeling after vascular injury (183).…”

Inflammation, negative nitrogen balance, and outcome after aneurysmal subarachnoid hemorrhage

“…In previous studies, we and others have identified the importance of assessing free fatty acid metabolism and supplementation on the occurrence of DCI. 18,42,43 Protein energy malnutrition identified in this study may be another target for intervention with amino acid supplementation. Prospective studies assessing the impact of specific amino acids and inflammation on outcome are needed to determine whether immunomodulation with nutritional supplementation may provide benefit after SAH.…”

Elevated concentrations of sphingosylphosphorylcholine in cerebrospinal fluid after subarachnoid hemorrhage: A possible role as a spasmogen

“…We used the method of Shirao et al 11 Briefly, adult mongrel dogs were sedated by the intraperitoneal administration of sodium pentobarbital (25 mg/kg) and allowed to breathe spontaneously. The right femoral artery was punctured percutaneously by the Seldinger technique.…”

“…They also showed that the Rho-kinase inhibitors Y27632 and eicosapentaenoic acid (EPA) inhibited both SPC-induced vasoconstriction and CV after SAH induction. 11 Thus, we hypothesize that an increase in the concentration of SPC in cerebrospinal fluid (CSF) following SAH may mediate the SPC-Rho-kinase pathway and cause CV.…”