Nitric oxide synthase activity and inhibition after neonatal hypoxia ischemia in the mouse brain

Despite the emergence of therapies for hypaxic-ischemic injury to the matur e nervous system, there have been no proven efficacious therapies for the d eveloping nervous system. Recent studies have shown that pharmacological bl ockade of neuronal nitric oxide synthase (nNOS) activity can ameliorate dam age after ischemia in the mature rodent. We have previously shown that elim ination of nNOS neurons, either by targeted disruption of the gene or by ph armacological depletion with intraparenchymal quisqualate, can decrease inj ury after hypoxia-ischemia. Using a simpler pharmacological approach, we st udied the efficacy of a systemically administered NOS inhibitor, 7-nitroind azole, a relatively selective inhibitor of nNOS activity. Using multiple do ses and concentrations administered after the insult, we found that there w as only a trend for protection with higher doses of the drug. A significant decrease in NOS activity was seen at 18 h and 5 days in the cor rex, and a t ? h and 18 h in the hippocampus after the hypoxia-ischemia, nNOS expressi on decreased and remained depressed for at least 18 h after the insult. Whe n nNOS expression was normalized to MAP2 expression, a decrease was seen at Is h in the cortex and at 2 and 18 h in the hippocampus. These data sugges t that further inhibition of NOS activity at early timepoints may not provi de substantial benefit. At 5 days after the insult, however, NOS activity a nd normalized nNOS expression returned to baseline or higher in the hippoca mpus, the region showing the most damage. These data suggest that delayed a dministration of nNOS inhibitor after hypoxic-ischemic injury might be bene ficial. (C) 2000 Elsevier Science B.V. All rights reserved.