AMPA, but not NMDA, receptor antagonism is neuroprotective in gerbil global ischaemia, even when delayed 24 h.
The selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) and the selective N-methyl-D-aspartate (NMDA) receptor antagonists MK 801 and ifenprodil were administered to Mongolian gerbils following a 5 min period of bilateral carotid artery occlusion. NBQX when given 4, 6 or 24 h after ischaemia gave a reduced loss of hippocampal CA1 neurones compared to control animals receiving vehicle only. Dizocilipine (MK 801) (1-10 mg/kg i.p.) and ifenprodil (a total of 45 mg/kg i.p.) gave no protection. The peak levels of NBQX obtained in the cerebrospinal fluid of gerbils receiving the neuroprotective dose (3 x 30 mg/kg i.p.) was 1 microM. In gerbil cortex slices, this concentration had no effect on NMDA-evoked depolarization, but had a moderate effect on kainate and gave a total blockade of AMPA depolarizations. It is concluded that antagonists of non-NMDA glutamate receptor subtypes, possibly AMPA, may be a useful therapeutic approach for cerebral ischaemia-related brain damage following global ischaemia.
Sheardown
M J
MJ
Novo Nordisk A/S, Pharmaceuticals Research, Novo Nordisk Park, Måløv, Denmark.
Suzdak
P D
PD
Nordholm
L
L
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists; D005260:Female; D005849:Gerbillinae; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D007051:Ibotenic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007700:Kinetics; D008297:Male; D009474:Neurons / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000494:pharmacology; D011810:Quinoxalines / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D018091:Receptors, AMPA; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D011810:Quinoxalines; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D007051:Ibotenic Acid; D016291:Dizocilpine Maleate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C010739:ifenprodil