gamma-Acetylenic GABA produces axon-sparing neurodegeneration after focal injection into the rat hippocampus.
In exploring the recently discovered phenomenon of indirect excitotoxicity, we noted that intrahippocampal injections of the nonspecific aminotransferase inhibitor gamma-acetylenic GABA (GAG; 60-240 nmol) caused excitotoxic lesions in rats. When assessed 3 days following the injection, GAG was shown to be approximately equally toxic to CA3/hilar neurons and CA1 pyramids, while CA2 neurons and granule cells were clearly less vulnerable. Choline acetyltransferase activity, a marker of extrinsic afferents, remained unchanged in the GAG-lesioned hippocampus, indicating the axon-sparing nature of the insult. In contrast, a lesion caused by 240 nmol of GAG resulted in a significant reduction in 3H-MK-801 binding, which was used as a marker for NMDA receptor-bearing hippocampal neurons. GAG-induced lesions were blocked by the NMDA receptor antagonists MK-801 and AP7 but were not influenced by the nature of the anesthetic used during surgery. Iontophoretic application of GAG did not excite CA1/CA3 cells in the rat hippocampus. In vitro, GAG proved to be a relatively potent inhibitor (IC50: 43 microM) of kynurenine aminotransferase, the biosynthetic enzyme of the endogenous neuroprotectant kynurenic acid. GAG also inhibited the neosynthesis of kynurenic acid in hippocampal slices (IC50: 790 microM). Thus, GAG shares several characteristics of the recently described indirect excitotoxin aminooxyacetic acid (AOAA; Exp. Neurol. 113: 378, 1991). GAG and AOAA appear to belong to a new family of excitotoxic agents which produce lesions indirectly by metabolic derangement and/or inhibition of kynurenate production.
McMaster
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Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore 21228.
Baran
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Wu
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French
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Schwarcz
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D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors; D000480:Alkynes; D000596:Amino Acids / Q000494:pharmacology; D000614:Aminocaproates / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001369:Axons / Q000187:drug effects* / Q000648:ultrastructure; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D007736:Kynurenic Acid / Q000378:metabolism; D008190:Lyases; D008297:Male; D009410:Nerve Degeneration / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013238:Stereotaxic Techniques; D000637:Transaminases / Q000378:metabolism
D000480:Alkynes; D000596:Amino Acids; D000614:Aminocaproates; D000927:Anticonvulsants; D016194:Receptors, N-Methyl-D-Aspartate; C013785:4-amino-5-hexynoic acid; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D002795:Choline O-Acetyltransferase; D000637:Transaminases; D000612:4-Aminobutyrate Transaminase; C427605:glutamine - phenylpyruvate transaminase; C021481:kynurenine-oxoglutarate transaminase; D008190:Lyases; D007736:Kynurenic Acid; C031231:2-amino-7-phosphonoheptanoic acid