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The glutamate antagonist MK‐801 reduces focal ischemic brain damage in the rat
Author(s) -
Park C. K.,
Nehls D. G.,
Graham D. I.,
Teasdale G. M.,
McCulloch J.
Publication year - 1988
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410240411
Subject(s) - nmda receptor , anesthesia , ischemia , medicine , caudate nucleus , glutamate receptor , neurochemical , middle cerebral artery , antagonist , occlusion , cerebral cortex , brain damage , receptor
Excessive activation of the N ‐methyl‐D‐aspartate (NMDA) subtype of glutamate receptor has been implicated in the sequence of neurochemical events that results in irreversible neuronal damage in cerebral ischemia. The effects of the NMDA antagonist (+) ‐5‐methyl‐10,ll‐dihydro‐5H‐dibenzo[a,d]cyclohepten‐5,10‐imine maleate (MK‐801) upon the amount of ischemic brain damage has been assessed quantitatively in the lightly anesthetized rat. Focal cerebral ischemia was produced by the permanent occlusion of one middle cerebral artery (MCA), and the animals were killed 3 hours after the arterial occlusion. MK‐801 (0.5 mg/kg) was administered intravenously either 30 minutes prior to MCA occlusion or 30 minutes after the induction of ischemia. Pretreatment with MK‐801 reduced the volume of ischemic damage both in the cerebral cortex (by 38% compared with untreated rats with MCA occlusion; p < 0.01) and in the caudate nucleus (by 18% compared with controls; p < 0.05). Treatment with MK‐801, initiated 30 minutes after MCA occlusion, reduced the volume of ischemic damage in the cerebral cortex (by 52% compared with controls; p < 0.01). The volume of ischemic damage in the caudate nucleus was minimally influenced by MK‐801 treatment initiated after MCA occlusion. The antiischemic effects of MK‐801 were readily demonstrable despite the hypotension that MK‐801 induced in rats anesthetized with halothane (0.5%), nitrous oxide (70%), and oxygen (30%). The potency of MK‐801 in reducing ischemic brain damage, even when administered after the induction of ischemia, highlights the potential use of NMDA receptor antagonists for the treatment of focal cerebral ischemia in humans.