IN-VIVO HYPOXIA-INDUCED NEURONAL DAMAGE WITH AN ENHANCEMENT OF NEURONAL NITRIC-OXIDE SYNTHASE IMMUNOREACTIVITY IN HIPPOCAMPUS

Although it is well known that brain ischemia is dominantly caused by hypoxia and hypoglycemia, it is still unclear how hypoxia participates in ischemia. We studied the changes in neuronal nitric oxide synthase (nNOS) and the effect of the NOS inhibitor N-G-nitro-L-arginine (NNA) on hypoxia. In vivo hypoxia (5% O-2/95% N-2 for 30 min) induced mild degenerative neuronal changes (shrunken and eosinophilic somata with p icnotic nuclei) in neurons of the CA3, the hilus of the dentate gyrus (DG) and the DC;, but not in the CA1. At 3 and 7 days after hypoxia, l evels of nNOS protein were significantly enhanced to 153 and 209%, but iNOS protein could not be detected. The numbers of nNOS-immunopositiv e neurons were significantly enhanced to 145 and 191% in the CA3, 145 and 178% in the hilus of the DG:, and 243 and 387% in the DG after 3 a nd 7 days, respectively. In contrast, no statistical difference was de termined in the CA1. We further examined the effect of NNA administere d at 5 min and 3, 6, and 24 h after hypoxia. Administration of MNA (0. 1 and 1 mg/kg, ip) significantly decreased the number of damaged neuro ns in the hilus of the DG and the DG;. However, higher doses of NNA (1 0 mg/kg, ip) did not prevent damage. These results suggest that hypoxi a alone induces enhancement of nNOS protein and nNOS immunoreactivity in neurons of the hippocampus and that NNA has biphasic effects agains t hypoxia-induced neuronal damage in the hilus of the DG and the DG. ( C) 1997 Academic Press.