Simvastatin Treatment Duration and Cognitive Preservation in Experimental Subarachnoid Hemorrhage

Abstract

Cognitive dysfunction, a significant complication after subarachnoid hemorrhage (SAH), affects up to 60% of survivors. We hypothesized that oral simvastatin would improve vestibulomotor function and reduce cognitive dysfunction after experimental SAH in the rat, and explored the effects of simvastatin on vasospasm and regional cerebral blood flow (rCBF). In total 160 rats were enrolled. Randomization to simvastatin or vehicle occurred after double intracisternal blood injections. Effects of simvastatin 10 mg/kg/d (SV10), simvastatin 1.5 mg/kg/d, or vehicle on rotarod, Morris water maze, neuronal survival, cerebral arterial diameter, and rCBF were determined by a blinded observer (n=15/group). A dose dependent response to simvastatin was observed, with more rapid improvement in vestibulomotor function, less basilar arterial vasospasm, and improved cortical neuronal survival with SV10. However, rotarod performance in the SV10 group deteriorated after 1 week, which correlated with the increased plasma creatine kinase levels (r=-0.737; P=0.0002). Furthermore, when simvastatin was discontinued after 2 weeks, the usual treatment duration in SAH clinical trials, rotarod performance deteriorated acutely, rCBF returned to control values, and no long-term benefit was observed in terms of visual spatial memory. Continuing simvastatin 1.5 mg/kg/d for 5 weeks resulted in sustained improvement in rotarod performance, reduced escape latency (P=0.001), swimming distance (P=0.002), and swimming speed (P=0.03) versus vehicle (n=12/group). Our results indicate that long-term cognitive dysfunction after experimental SAH in the rat can be reduced by simvastatin. However, treatment had to be extended beyond 2 weeks, the traditional risk period for angiographic vasospasm, to improve long-term outcome.