γ-acetylenic GABA produces axon-sparing neurodegeneration after focal injection into the rat hippocampus

Owen G. McMaster, Halina Baran, Hui Qiu Wu, Fu Du, Edward D. French, Robert Schwarcz

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

In exploring the recently discovered phenomenon of indirect excitotoxicity, we noted that intrahippocampal injections of the nonspecific aminotransferase inhibitor γ-acetylenic GABA (GAG; 60-240 nmol) caused excitotoxic lesions it, 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 axonsparing 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. Lontophoretic 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 μM) 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 μM). 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.

Original languageEnglish (US)
Pages (from-to)184-191
Number of pages8
JournalExperimental Neurology
Volume124
Issue number2
DOIs
StatePublished - Dec 1993

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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