Aminooxyacetic acid produces excitotoxic brain injury in neonatal rats.
Impairment of cellular energy metabolism plays an important role in the expression of brain injury resulting from a variety of acute neurologic disorders. The role of mitochondrial energy metabolism in excitotoxic perinatal brain injury was assessed by studying the toxicity of aminooxyacetic acid (AOAA), an inhibitor of mitochondrial malate-aspartate shunt, in postnatal (PND) 7 rats. Intrastriatal injection of AOAA produced seizures and dose-dependent excitotoxic injury. The neuronal damage was attenuated by pyridoxine suggesting involvement of pyridoxal dependent mechanisms. The lesion was selectively blocked by the NMDA antagonist MK-801 but not the AMPA antagonist GYKI-52466. Furthermore, AOAA potentiated NMDA, but not AMPA or 1S,3R-ACPD, induced brain injury. The data suggest that regional impairment of cellular energy metabolism is an important determinant of selective vulnerability to excitotoxic injury in perinatal rats. Furthermore, the role of impaired energy metabolism is particularly relevant to NMDA receptor mediated brain injury.
McDonald
J W
JW
CNS Research, Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, IN 46285.
Schoepp
D D
DD
D000625:Aminooxyacetic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D003342:Corpus Striatum; D016291:Dizocilpine Maleate / Q000494:pharmacology; D006624:Hippocampus; D007267:Injections; D009498:Neurotoxins / Q000494:pharmacology*; D011736:Pyridoxine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013238:Stereotaxic Techniques
D014151:Anti-Anxiety Agents; D009498:Neurotoxins; C061950:GYKI 52466; D001569:Benzodiazepines; D000625:Aminooxyacetic Acid; D016291:Dizocilpine Maleate; D011736:Pyridoxine