Effects of Cerebral Ischemia in Mice Deficient in Neuronal Nitric Oxide Synthase

TLDR

The role of nitric oxide in brain injury is debated, partly because nonselective inhibitors block NO production in neuronal, glial, and vascular cells. Neuronal NOS deficiency reduces infarct size and improves neurological outcomes after middle cerebral artery occlusion, whereas endothelial NOS inhibition worsens injury, indicating that neuronal NO exacerbates acute ischemia and underscoring the need for selective neuronal NOS inhibitors.

Abstract

The proposal that nitric oxide (NO) or its reactant products mediate toxicity in brain remains controversial in part because of the use of nonselective agents that block NO formation in neuronal, glial, and vascular compartments. In mutant mice deficient in neuronal NO synthase (NOS) activity, infarct volumes decreased significantly 24 and 72 hours after middle cerebral artery occlusion, and the neurological deficits were less than those in normal mice. This result could not be accounted for by differences in blood flow or vascular anatomy. However, infarct size in the mutant became larger after endothelial NOS inhibition by nitro-L-arginine administration. Hence, neuronal NO production appears to exacerbate acute ischemic injury, whereas vascular NO protects after middle cerebral artery occlusion. The data emphasize the importance of developing selective inhibitors of the neuronal isoform.