Introduction: Delayed cerebral ischemia is a major contributor to poor outcome after aneurysmal subarachnoid hemorrhage (SAH) and is multifactorial in etiology. Our prior proof-of-concept work demonstrated that preconditioning (PC), a powerful and pleiotropic phenomenon, is an effective multi-faceted strategy to combat DCI after SAH. In this study, we hypothesized that SIRT1 is a critical upstream inducer of PC-induced protection and may, therefore, represent an attractive therapeutic target.
Methods: Wild-type C57BL/6J mice were utilized in the study and subjected to normoxia or hypoxia (8% oxygen for 4hours). Surgical procedures included induction of SAH via endovascular perforation or sham surgery. Multiple endpoints were assessed including cerebral vasospasm, neurobehavioral deficits, SIRT1 expression via quantitative real-time PCR for mRNA, and western blot for protein quantification. Pharmacological agents utilized in the study include EX-527 (SIRT1 inhibitor), and Resveratrol (SIRT1 activator), and L-NNA (NOS inhibitor).
Results: SIRT1 expression was upregulated at 6, 12, 24, and 48 hours after hypoxic conditioning. SIRT1 inhibition with EX-527 resulted in a loss of PC-induced protection against vasospasm and neurobehavioral deficits after SAH. Resveratrol increased SIRT1 expression and induced NOS-dependent vasodilation in cerebral arterioles ex vivo. Resveratrol treatment resulted in a dose-dependent protection against vasospasm and neurobehavioral deficits after SAH. SIRT1 inhibition resulted in a loss of Resveratrol-induced protection, thereby suggesting that the protective effects of Resveratrol are SIRT1-mediated.
Conclusions: The multi-faceted protective effects of PC against SAH-induced neurovascular dysfunction is SIRT1 dependent. SIRT1 activation is a promising, novel, pleiotropic, therapeutic strategy to combat DCI after SAH.
Patient Care: This research identified SIRT1 as a therapeutic target to combat SAH-induced neurovascular dysfunction. Future studies are needed prior to clinical translation.
Learning Objectives: 1. Understand the pathogenesis of DCI after SAH.
2. Understand the pleiotropic effects of a conditioning strategy.
3. Understand the role of SIRT1 in SAH-induced neurovascular dysfunction.