Endothelial Nitric Oxide Synthase Mediates Endogenous Protection Against Subarachnoid Hemorrhage-Induced Cerebral Vasospasm

Vellimana AK, Milner E, Azad TD, Harries MD, Zhou ML, Gidday JM, Han BH, Zipfel GJ (2011). Stroke, 42(3):776-82 Read More

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(G)-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.

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Posted on October 12, 2011
Posted in: Axon Injury & Repair, HPAN, Neurodegeneration, Neurogenetics, Neurovascular Injury & Repair, Publications, Therapeutics & Diagnostics Authors: , ,