The N-methyl-D-aspartate (NMDA) receptor glycine site antagonist ACEA 1021 does not produce pathological changes in rat brain

被引:33
|
作者
Hawkinson, JE
Huber, KR
Sahota, PS
Hsu, HH
Weber, E
Whitehouse, MJ
机构
[1] CIBA GEIGY CORP, DIV PHARMACEUT, SUBDIV DRUG METAB & EXPLORATORY TOXICOL, PRECLIN SAFETY, SUMMIT, NJ 07901 USA
[2] CIBA GEIGY CORP, DIV PHARMACEUT, SUBDIV DRUG METAB & PATHOL, PRECLIN SAFETY, SUMMIT, NJ 07901 USA
关键词
N-methyl-D-aspartate receptor; glycine antagonist; ACEA; 1021; neurotoxicity; neuropathology; retrosplenial cortex; cingulate cortex;
D O I
10.1016/S0006-8993(96)01064-5
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
ACEA 1021 is a potent, selective N-methyl-D-aspartate (NMDA) receptor glycine site antagonist under clinical evaluation as a neuroprotectant for stroke and head trauma. The potential of ACEA 1021 to produce morphologic changes in cerebrocortical neurons of the rat was assessed since it is known that noncompetitive (e.g., MK-801) and competitive (e.g., CGS 19755) NMDA receptor antagonists produce neuronal vacuolization and necrosis in the rat posterior cingulate/retrosplenial cortex. Male and female adult rats were treated intravenously with either vehicle (Tris) or 10 mg/kg or 50 mg/kg ACEA 1021. MK-801 (5 mg/kg, s.c.) served as positive control. Whereas MK-801 produced characteristic neuronal vacuolization and necrosis in the posterior cingulate/retrosplenial cortex, neither dose of ACEA 1021 had any effect on neuronal morphology. The absence of neuropathological changes in rats supports the further clinical evaluation of ACEA 1021 for stroke and head trauma, and suggests that glycine site antagonists may be devoid of neurotoxic potential.
引用
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页码:227 / 234
页数:8
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