AMPA antagonists: do they hold more promise for clinical stroke trials than NMDA antagonists?
The cytoprotective effects of MK-801 and NBQX, selective N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonists, respectively, were compared both singularly and in combination in models of transient severe forebrain and transient focal cerebral ischemia. After 10 minutes of four-vessel occlusion ischemia, the sodium salt of NBQX (30 mg/kg IP) given at the time of reperfusion and, subsequently, 15 and 30 minutes later produced a dramatic reduction in CA1 hippocampal necrosis at 7 days. This effect was not obtained with the intraperitoneal administration of either MK-801 (1 mg/kg x 3) or the combination of both NBQX and MK-801 given at the same time intervals. This effect of intraperitoneal NBQX alone was reproduced in a two-vessel occlusion/hypotension model using this same drug administration. Delayed treatment with both NBQX and GYKI 52466, but neither MK-801 nor the combination of NBQX and MK-801 given after a delay, produced a significant reduction in the mean volume of neocortical infarction after transient focal ischemia. We conclude that the AMPA receptor may play a more important role than the NMDA receptor in both selective ischemic necrosis of hippocampal neurons and in neocortical infarction. AMPA antagonists should be subjected to clinical stroke trials.
Buchan
A M
AM
Department of Neurology-Neuroscience, University of Ottawa, Ottawa Civic Hospital, Ontario, Canada.
Lesiuk
H
H
Barnes
K A
KA
Li
H
H
Huang
Z G
ZG
Smith
K E
KE
Xue
D
D
D000818:Animals; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines / Q000008:administration & dosage / Q000627:therapeutic use*; D002544:Cerebral Infarction / Q000473:pathology; D002561:Cerebrovascular Disorders / Q000188:drug therapy*; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000627:therapeutic use; D004334:Drug Administration Schedule; D007274:Injections, Intraperitoneal; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D011810:Quinoxalines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000037:antagonists & inhibitors*
D014151:Anti-Anxiety Agents; D011810:Quinoxalines; C061950:GYKI 52466; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D001569:Benzodiazepines; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid