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

Abstract

In the present studies we have investigated the effects of a range of glycine site antagonists of the N-methyl-d-aspartate (NMDA) receptor in the gerbil model of global cerebral ischaemia. The compounds tested were (+)-3-amino-1-hydroxy-2-pyrrolidone (HA 966, 15 mg/kg), 7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(H)-quinolinone) (L-701,324, 40 mg/kg), 7-chloro-3-(cyclopropylcarbonyl)-4-hydroxy-2(1H)-quinolinone) (L-701, 252, 50 mg/kg), (3-(3-hydroxyphenyl)prop-2-ynyl 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-competitive NMDA antagonist, (5R,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-car boxylic acid (LY293558, 20 mg/kg). In the present studies L-701,252, L-701, 324 and L-701,273 provided a small degree of neuroprotection. ACEA 1021, GV 150526A and HA 966 failed 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 antagonists provide a small degree of neuroprotection in global cerebral ischaemia. In contrast, AMPA receptor antagonists provide more robust neuroprotection in global cerebral ischaemia.