Premium
Aminooxyacetic Acid Results in Excitotoxin Lesions by a Novel Indirect Mechanism
Author(s) -
Beal M. Flint,
Swartz Kenton J.,
Hyman Bradley T.,
Storey Elsdon,
Finn Stephen F.,
Koroshetz Walter
Publication year - 1991
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1991.tb08258.x
Subject(s) - aminooxyacetic acid , excitotoxicity , quinolinic acid , nmda receptor , ibotenic acid , glutamate receptor , neurotoxin , neuroscience , pharmacology , biology , riluzole , chemistry , endocrinology , biochemistry , receptor , central nervous system , enzyme , tryptophan , amino acid
Aminooxyacetic acid (AOAA) is an inhibitor of several pyridoxal phosphate‐dependent enzymes in the brain. In the present experiments intrastriatal injections of AOAA produced dose‐dependent excitotoxic lesions. The lesions were dependent on a pyridoxal phosphate mechanism because pyridoxine blocked them. The lesions were blocked by the noncompetitive N ‐methyl‐D‐aspartate (NMDA) antagonist MK‐801 and by coinjection of kynurenate, a result indicating an NMDA receptor‐mediated excitotoxic process. Electrophysiologic studies showed that AOAA does not directly activate ugand‐gated ion channels in cultured cortical or striatal neurons. Pentobarbital anesthesia attenuated the lesions. AOAA injections resulted in significant increases in lactate content and depletions of ATP levels. AOAA striatal lesions closely resemble Huntington's disease both neurochemically and histologically because they show striking sparing of NADPH‐diaphorase and large neurons within the lesioned area. AOAA produces excitotoxic lesions by a novel indirect mechanism, which appears to be due to impairment of intracellular energy metabolism, secondary to its ability to block the mitochondrial malate‐aspartate shunt. These results raise the possibility that a regional impairment of intracellular energy metabolism may secondarily result in excitotoxic neuronal death in chronic neurodegenerative illnesses, such as Huntington's disease.