Evaluation of glycine site antagonists of the NMDA receptor in global cerebral ischaemia

In the present studies we have investigated the effects of a range of glyci ne site antagonists of the N-methyl-D-aspartate (NMDA) receptor in the gerb il model of global cerebral ischaemia. The compounds tested were (+)-3-amin o-1-hydroxy-2-pyrrolidone (HA 966, 15 mg/kg), 7-chloro-4-hydroxy-3-(3-pheno xy)phenyl-2 (L-701,324, 40 mg/kg), 7-chloro-3-(cyclopropylcarbonyl)-4-hydro xy-2(1H)-quinolinone) (L-701,252, 50 mg/kg), (3-(3-hydroxyphenyl)prop-2-yny l 7-chloro-4 hydroxy-2(1H)-quinolone-3-carboxylate) (L-701,273, 50 mg/kg), 5-nitro-6,7-dichloro-2,3-quinoxalinedione (ACEA 1021, 25 mg/kg) and [(E)-3[ (phenylcarbamoyl)ethenyl]-4,6-dichloroindole-2-carboxylic acid sodium salt (GV 150526A, 40 mg/kg). All compounds were administered via the i.p. route 30 min before and again at 2 h 30 min after 5 min bilateral carotid artery occlusion (BCAO) in the gerbil. For comparison we also evaluated a non-comp etitive NMDA antagonist, (5 R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[ a, d]cyclohepten-5, 10-imine (MK-801, 2 mg/kg) and an alpha-amino-3-hydroxy -5-methylisoxazole-4-propionic acid(AMPA) antagonist, (3S,4aR, 6R, 8aR)-6-[ 2-(1(2)H-tetrazole-5-yl)]decahydroisoquinoline-3-carboxylic acid(LY293558, 20 mg/kg). In the present studies L-701,252, L-701,324 and L-701,273 provid ed a small degree of neuroprotection. ACEA 1021, GV 150526A and HA 966 fail ed to provide any neuroprotection, while MK-801 provided significant (20%) protection. In contrast LY293558 provided good (55%) neuroprotection. These results indicate that glycine site antagonists and competitive NMDA antago nists provide a small degree of neuroprotection in global cerebral ischaemi a. In contrast, AMPA receptor antagonists provide more robust neuroprotecti on in global cerebral ischaemia. (C) 1999 Elsevier Science B.V. All rights reserved.