Nitric Oxide

Studies of neuronal cultures have indicated a key role for NO in the excitotoxic actions of NMDA (66). The neuronal isoform of NOS (nNOS) is linked to NMDA receptors by postsynaptic den-sity-95 protein, thereby permitting activity to be controlled by Ca2+ influx through the NMDA receptor-channel complex. Overexcitation of NMDA receptors during ischemia and reperfusion leads to bursts of NO production, which can alter protein function by nitrosylation of cysteine residues and nitration of tyrosine residues. Furthermore, if superoxide production is amplified during reoxygenation, increased NO and superoxide will generate toxic levels of peroxynitrite. In focal ischemia, loss of the nNOS isoform is protective, whereas loss of the endothelial NOS isoform worsens injury (67,68). The latter effect is thought to be related to the vasodilatory and antiplatelet aggregatory effects of NO. Early attempts to assess the role of NO in global ischemia models generally revealed no protection in hippocampal pyramidal neurons or cerebellar Purkinje neurons by administration of nonselective NOS inhibitors (30,69-71), although one study did find hippocampal protection with short (5 min) ischemic duration (72) and another study found decreased blood-brain barrier permeability (73). However, studies with gene deletion of nNOS or with administration of a selective nNOS inhibitor reported protection in the hippocampal CA1 region (74,75). Increases in NO production have been measured during forebrain ischemia ( 76 ) and specifically in hippocampus during reperfusion (77). The increase in hippocampal NO production persisted over a 3-hr observation period after 10 or 15 min of global ischemia and was blocked by a selective nNOS inhibitor (77). However, the inhibitor provided hippocampal protection after 5 min of ischemia but not after 10 min of ischemia. Therefore, despite the lack of efficacy of NMDA receptor antagonists and nonselective NOS inhibitors in most studies of global cerebral ischemia, neuronally derived NO appears to contribute to hippocampal injury. However, inconsistent efficacy with inhibition of the neuronal isoform after moderately prolonged ischemia indicates the importance of other mechanisms in triggering cell death.

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