Evaluation of glycine site antagonists of the NMDA receptor in global cerebral ischemia
4区 · 医学
作者: Hicks, Caroline A. ; Ward, Mark A. ; Ragumoorthy, Nella ; Ambler, Samantha J. ; Dell, Colin P. ; Dobson, David ; O'Neill, Michael J.
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.
1997-01-09·Brain Research4区 · 医学
The glycine site of the NMDA receptor contributes to neurokinin1 receptor agonist facilitation of NMDA receptor agonist-evoked activity in rat dorsal horn neurons
4区 · 医学
作者: Heppenstall, P. A. ; Fleetwood-Walker, S. M.
We have investigated the role of the glycine recognition site of the N-methyl-D-aspartate receptor (the GlyNMDA site) in the facilitation of NMDA receptor agonist-evoked activity in rat dorsal horn neurons that is brought about by neurokinin1 (NK1) receptor agonist and the contribution of protein kinase C (PKC) activation to this phenomenon. Ionophoresis of the selective NMDA receptor agonist 1-aminocyclobutane-cis-1,3-dicarboxylic acid (ACBD) produced a sustained increase in the firing rate of single laminae III-V neurons recorded extracellularly using multibarrelled glass electrodes. The highly selective NK1 receptor agonist acetyl-[Arg6,Sar9,Met(O2)11]-SP6-11 (Sar9-SP) greatly facilitated this response, but under the present conditions had no effect when applied alone or with alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor agonist) at the same current. In the presence of the GLyNMDA site antagonists 2-carboxy-4,6-dichloro-(1H)-indole-3-propanoic acid (MDL 29951), 7-chloro-3-(cyclopropylcarbonyl)-4-hydroxy-2(1H)-quinoline (L701,252), 5,7-dinitroquinaxoline-2,3-dione (MNQX) or 7-chlorothiokynurenic acid (7-CTK), or the PKC inhibitors, chelerythrine or GF109203X, the Sar9-SP-induced facilitation of ACBD-evoked activity was prevented, generally restoring activity to a level similar to that in the presence of ACBD alone, whilst an AMPA receptor antagonist, 6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione (NBQX) did not inhibit the facilitation. At the same ionophoretic currents these compounds had no effect on ACBD-evoked activity in the absence of Sar9-SP but were inhibitory at significantly greater currents. To further substantiate the importance of the GlyNMDA site in the interaction, the effects of NMDA receptor antagonists selective for alternative recognition sites on the NMDA receptor were investigated. MK-801, a non-competitive NMDA receptor antagonist and arcaine, a competitive inhibitor at the polyamine site, were applied to the facilitated activity seen in the presence of Sar9-SP and ACBD, and to ACBD-evoked activity alone. Unlike the GlyNMDA site antagonists and PKC inhibitors, these compounds reduced both facilitated and ACBD-evoked activity at similar currents. Furthermore, like the NK1 receptor agonist, a selective GlyNMDA site agonist 1-aminocyclopropane carboxylic acid (ACPC) caused facilitation of ACBD-evoked activity which was also blocked by currents of L701,252 that did not alter activity evoked by ACBD alone. These data suggest that activation of the GlyNMDA site (perhaps as a consequence of glycine release or modification of its influence by intracellular signalling cascades) is an essential component of the means by which NK1 receptor activation results in facilitated responsiveness of dorsal horn neurons towards NMDA receptor agonists.