The neuroprotective glycine receptor antagonist GV150526 does not produce neuronal vacuolization or cognitive deficits in rats

The neuroprotective activity of the novel glycine receptor antagonist (E)-3 [(phenylcarbamoil)ethenil]-4,6-dichloroindole-2-carboxylic acid sodium salt ) (GV150526) was recently reported in a model of focal ischemia in the rat. Here it was investigated whether GV150526 treatment results in any of the adverse side effects commonly detected after injection of NMDA (N-methyl-D- aspartate) receptor antagonists. First, it was found that neuronal vacuoliz ation in the posterior cingulate/retrosplenial area of the cortex was not i nduced by GV150526 (200 mg/kg, i.v.), but was evident after injection of th e NMDA receptor antagonist dizocilpine (MK801) (1 mg/kg, s.c.). In a second set of experiments, the effects of GV150526 were examined on perforant pat h-dentate gyrus long-term potentiation in rats. GV150526 (3 mg/kg, i.v.) in jected 30 min or 150 min prior to tetanization did not block potentiation o f the e.p.s.p. slope and population spike amplitude. In contrast, in animal s treated with MK801 (1 mg/kg, i.p.) 150 min before tetanization there was a clear block of long-term potentiation of the e.p.s.p. slope and populatio n spike amplitude. The effects of GV150526 were also examined in the Morris Water Maze. Rats injected with GV150526 (10 mg/kg or 60 mg/kg, p.o,) did n ot show any impairment in learning when compared to control. MK801 (0.08 mg /kg, i.p.), on the other hand, significantly affected the ability to locate the escape platform in the Water Maze. These findings show that GV150526 i s devoid of adverse side effects even at doses well above those producing a neuroprotective effect. This drug has therapeutic potential with a much gr eater margin of safety than NMDA channel blockers or competitive NMDA recep tor antagonists. (C) 1999 Elsevier Science B.V. All rights reserved.