SELECTIVE DESTRUCTION OF NITRIC-OXIDE SYNTHASE NEURONS WITH QUISQUALATE REDUCES DAMAGE AFTER HYPOXIA-ISCHEMIA IN THE NEONATAL RAT

The vulnerability of the developing CNS to hypoxia-ischemia (H-I) diff ers from that of the mature brain and is due in part to release of nit ric oxide (NO) from parenchymal neurons. If NO is important in the gen eration of excitotoxic injury after H-I in the developing CNS, then se lective destruction of the neuronal nitric oxide synthase (nNOS) cells before H-I should lessen the injury seen after the insult. Using low dose quisqualic acid (QA) injected into neonatal (postnatal d 7) parie tal cortex, the nNOS neurons were eliminated while sparing other neuro nal and glial populations as ascertained by NADPH diaphorase histochem istry, nNOS immunocytochemistry, and Nissl counterstain. Animals subje cted to focal ischemia followed by global hypoxia 24 h after the intra cortical injection of QA had more viable cortex remaining than vehicle -injected animals (83.4 +/- 4.3% versus 62.7 +/- 8.3%) and lower injur y severity represented by less neuronal loss and gliosis. Intracortica l injections of QA without H-I resulted in minimal cell loss at the in jection site with elimination of nNOS neurons throughout the parietal cortex. Microglial and astrocytic proliferation was seen in areas dama ged by H-I 3 wk after injury and clearly marked infarcted areas. Preve ntion or elimination of NO production from nNOS cells can prevent much of the delayed neuronal necrosis seen after H-I in the developing CNS .