SIRT1 Activation Promotes Long-Term Functional Recovery After Subarachnoid Hemorrhage in Rats.

Abstract

An increase in sirtuin 1 (SIRT1) reportedly attenuates early brain injury, delayed cerebral ischemia, and short-term neurologic deficits in rodent models of subarachnoid hemorrhage (SAH). This study investigates the effect of resveratrol, a SIRT1 activator, on long-term functional recovery in a clinically relevant rat model of SAH. Thirty male Wistar rats were subjected to fresh arterial blood injection into the prechiasmatic space and randomized to receive 7days of intraperitoneal resveratrol (20mg/kg) or vehicle injections. Body weight and rotarod performance were measured on days 0, 3, 7, and 34 post SAH. The neurologic score was assessed 7 and 34days post SAH. Morris water maze performance was evaluated 29-33days post SAH. Brain SIRT1 activity and CA1 neuronal survival were also assessed. Blood pressure rapidly increased in all SAH rats, and no between-group differences in blood pressure, blood gases, or glucose were detected. SAH induced weight loss during the first 7days, which gradually recovered in both groups. Neurologic score and rotarod performance were significantly improved after resveratrol treatment at 34days post SAH (p = 0.01 and 0.04, respectively). Latency to find the Morris water maze hidden platform was shortened (p = 0.02). In the resveratrol group, more CA1 neurons survived following SAH (p = 0.1). An increase in brain SIRT1 activity was confirmed in the resveratrol group (p < 0.05). Treatment with resveratrol for 1week significantly improved the neurologic score, rotarod performance, and latency to find the Morris water maze hidden platform 34days post SAH. These findings indicate that SIRT1 activation warrants further investigation as a mechanistic target for SAH therapy.