Nitric Oxide Synthase in Models of Focal Ischemia

BACKGROUND AND PURPOSE: Cessation of blood flow to the brain, for even a few minutes, sets in motion a potential reversible cascade of events resulting in neuronal cell death. Oxygen free radicals and oxidants appear to play an important role in central nervous system injury after cerebral ischemia and reperfusion. Recently, divergent roles for the newly identified neuronal messenger molecule and oxygen radical, nitric oxide (NO), have been identified in various models of cerebral ischemia. Because of the chemical and physical properties of NO, the numerous physiological activities it mediates, and the lack of specific agents to modulate the activity of the different isoforms of NO synthase (NOS), reports regarding the role of NO in focal cerebral ischemia have been confounding and often conflicting. Recent advances in pharmacology and the development of transgenic knockout mice specific for the different isoforms of NOS have advanced our knowledge and clarified the role of NO in cerebral ischemia. METHODS: Animal models of focal ischemia employ occlusion of nutrient cerebral vessels, most commonly the middle cerebral artery. Primary cortical cultures are exposed to excitotoxic or ischemic conditions, and the activities of NOS isoforms or NO production are evaluated. Transgenic mice lacking expression of either the neuronal isoform of NOS (nNOS), the endothelial isoform of NOS (eNOS), or the immunologic isoform of NOS (iNOS) have been examined in models of excitotoxic injury and ischemia. RESULTS: Excitotoxic or ischemic conditions excessively activate nNOS, resulting in concentrations of NO that are toxic to surrounding neurons. Conversely, NO generated from eNOS is critical in maintaining cerebral blood flow and reducing infarct volume. iNOS, which is not normally present in healthy tissue, is induced shortly after ischemia and contributes to secondary late-phase damage. CONCLUSIONS: Pharmacological and genetic approaches have significantly advanced our knowledge regarding the role of NO and the different NOS isoforms in focal cerebral ischemia. nNOS and iNOS play key roles in neurodegeneration, while eNOS plays a prominent role in maintaining cerebral blood flow and preventing neuronal injury.