THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR GLYCINE SITE ANTAGONIST ACEA-1021 DOES NOT PRODUCE PATHOLOGICAL-CHANGES IN RAT-BRAIN

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 mor phologic changes in cerebrocortical neurons of the rat was assessed si nce it is known that noncompetitive (e.g., MK-801) and competitive (e. g., CGS 19755) NMDA receptor antagonists produce neuronal vacuolizatio n and necrosis in the rat posterior cingulate/retrosplenial cortex. Ma le and female adult rats were treated intravenously with either vehicl e (Tris) or 10 mg/kg or 50 mg/kg ACEA 1021. MK-801 (5 mg/kg, s.c.) ser ved as positive control. Whereas MK-801 produced characteristic neuron al vacuolization and necrosis in the posterior cingulate/retrosplenial cortex, neither dose of ACEA 1021 had any effect on neuronal morpholo gy. The absence of neuropathological changes in rats supports the furt her clinical evaluation of ACEA 1021 for stroke and head trauma, and s uggests that glycine site antagonists may be devoid of neurotoxic pote ntial.