Abstract
BACKGROUND AND PURPOSE - Vasospasm-induced delayed cerebral ischemia remains a major source of morbidity in patients with aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that activating innate neurovascular protective mechanisms by preconditioning (PC) may represent a novel therapeutic approach against SAH-induced vasospasm and neurological deficits and, secondarily, that the neurovascular protection it provides is mediated by endothelial nitric oxide synthase (eNOS). METHODS - Wild-type mice were subjected to hypoxic PC or normoxia followed 24 hours later by SAH. Neurological function was analyzed daily; vasospasm was assessed on post-surgery Day 2. Nitric oxide availability, eNOS expression, and eNOS activity were also assessed. In a separate experiment, wild-type and eNOS-null mice were subjected to hypoxic PC or normoxia followed by SAH and assessed for vasospasm and neurological deficits. RESULTS - PC nearly completely prevented SAH-induced vasospasm and neurological deficits. It also prevented SAH-induced reduction in nitric oxide availability and increased eNOS activity in mice with and without SAH. PC-induced protection against vasospasm and neurological deficits was lost in wild-type mice treated with the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester and in eNOS-null mice. CONCLUSIONS - Endogenous protective mechanisms against vasospasm exist, are powerful, and can be induced by PC. eNOS-derived nitric oxide is a critical mediator of PC-induced neurovascular protection. These data provide strong "proof-of- principle" evidence that PC represents a promising new strategy to reduce vasospasm and delayed cerebral ischemia after SAH.
Original language | English |
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Pages (from-to) | 776-782 |
Number of pages | 7 |
Journal | Stroke |
Volume | 42 |
Issue number | 3 |
DOIs | |
State | Published - Mar 2011 |
Keywords
- cerebral vasospasm
- hypoxia
- nitric oxide synthase
- preconditioning
- subarachnoid hemorrhage