AMPA antagonists: do they hold more promise for clinical stroke trials than NMDA antagonists?

Abstract

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.

• Authors: A M Buchan, H Lesiuk, K A Barnes, H Li, Z G Huang, K E Smith, D Xue
• Journal: Stroke (Stroke) Vol. 24 Issue 12 Suppl Pg. I148-52 (Dec 1993) ISSN: 0039-2499 [Print] United States
• PMID: 7504338 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Anxiety Agents
• Quinoxalines
• GYKI 52466
• 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
• Benzodiazepines
• N-Methylaspartate
• Dizocilpine Maleate
• alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

Topics

• Animals
• Anti-Anxiety Agents
• Benzodiazepines (administration & dosage, therapeutic use)
• Cerebral Infarction (pathology)
• Cerebrovascular Disorders (drug therapy)
• Dizocilpine Maleate (administration & dosage, therapeutic use)
• Drug Administration Schedule
• Injections, Intraperitoneal
• Male
• N-Methylaspartate (antagonists & inhibitors)
• Quinoxalines (administration & dosage, therapeutic use)
• Rats
• Rats, Wistar
• Reperfusion
• alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (antagonists & inhibitors)