Glutamate receptor antagonists in experimental focal cerebral ischaemia.
Excessive activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor has been implicated in the sequence of neurochemical events in cerebral ischaemia that results in irreversible neuronal damage. The effects of the NMDA antagonist MK-801 upon the amount of ischaemic brain damage has been assessed quantitatively in a cat and in a rat model of focal cerebral ischaemia. In chloralose-anaesthetised cats, focal cerebral ischaemia was produced by permanent occlusion of one middle cerebral artery (MCA) and the animal sacrificed 6 hours later. Pretreatment with the non-competitive NMDA antagonist, MK-801 (5 mg/kg, i.v.) reduced significantly the volume of ischaemic damage in the cerebral cortex by 57% compared to vehicle-treated cats. A similar degree of neuroprotection could be demonstrated in the cat MCA occlusion model if treatment with MK-801 was initiated 2 hours after the induction of ischaemia. In halothane-anaesthetised rats, focal cerebral ischaemia was produced by permanent MCA occlusion and the animals sacrificed 3 hours later. Pretreatment with MK-801 (0.5 mg/kg, i.v.) reduced the volume of ischaemic damage in the cerebral cortex by 38%; treatment with MK-801 initiated 30 minutes after MCA occlusion was equally effective in reducing cortical damage. In contrast to calcium entry blockers such as nimodipine in the rat MCA occlusion model, the improved histopathological outcome with MK-801 is not associated with improvement in cerebral tissue perfusion to the ischaemic tissue. The increasing evidence that NMDA receptor antagonists are beneficial in experimental focal cerebral ischaemia is reviewed.
McCulloch
J
J
Wellcome Neuroscience Group, Wellcome Surgical Institute, University of Glasgow, U.K.
Ozyurt
E
E
Park
C K
CK
Nehls
D G
DG
Teasdale
G M
GM
Graham
D I
DI
D000818:Animals; D001925:Brain Damage, Chronic / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology*; D002415:Cats; D002421:Caudate Nucleus / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004292:Dominance, Cerebral / Q000187:drug effects / Q000502:physiology; D008297:Male; D009553:Nimodipine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology
D016194:Receptors, N-Methyl-D-Aspartate; D009553:Nimodipine; D016291:Dizocilpine Maleate