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) differs from that of the mature brain and is due in part to release of nitric oxide (NO) from parenchymal neurons. If NO is important in the generation of excitotoxic injury after H-I in the developing CNS, then selective 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) parietal cortex, the nNOS neurons were eliminated while sparing other neuronal and glial populations as ascertained by NADPH diaphorase histochemistry, nNOS immunocytochemistry, and Nissl counterstain. Animals subjected to focal ischemia followed by global hypoxia 24 h after the intracortical injection of QA had more viable cortex remaining than vehicle-injected animals (83.4 +/- 4.3% versus 62.7 +/- 8.3%) and lower injury severity represented by less neuronal loss and gliosis. Intracortical injections of QA without H-I resulted in minimal cell loss at the injection site with elimination of nNOS neurons throughout the parietal cortex. Microglial and astrocytic proliferation was seen in areas damaged by H-I 3 wk after injury and clearly marked infarcted areas. Prevention or elimination of NO production from nNOS cells can prevent much of the delayed neuronal necrosis seen after H-I in the developing CNS.
Ferriero
D M
DM
Department of Neurology, University of California, San Francisco 94143-0114, USA.
Sheldon
R A
RA
Black
S M
SM
Chuai
J
J
D000818:Animals; D000831:Animals, Newborn; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002534:Hypoxia, Brain / Q000188:drug therapy* / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D016318:Quisqualic Acid / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018696:Neuroprotective Agents; D016318:Quisqualic Acid; D019001:Nitric Oxide Synthase