TY - JOUR
T1 - γ-acetylenic GABA produces axon-sparing neurodegeneration after focal injection into the rat hippocampus
AU - McMaster, Owen G.
AU - Baran, Halina
AU - Wu, Hui Qiu
AU - Du, Fu
AU - French, Edward D.
AU - Schwarcz, Robert
PY - 1993/12
Y1 - 1993/12
N2 - 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.
AB - 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.
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U2 - 10.1006/exnr.1993.1188
DO - 10.1006/exnr.1993.1188
M3 - Article
C2 - 8287921
AN - SCOPUS:0027787902
SN - 0014-4886
VL - 124
SP - 184
EP - 191
JO - Experimental Neurology
JF - Experimental Neurology
IS - 2
ER -