Prolonged Ischemic Cerebral Infarct in the Rat after Middle Cerebral Artery Occlusion: Part 2:Effect of the NMDA Antagonist, MK-801, Upon Ischemic Evolution

Park, Chun Kun; Kang, Joon Ki; Song, Jin Un

Abstract

Excessive activation of the N-methy-D-aspartate(NMDA) subtype of glutamate receptor, has been implicated in the sequence of neurochemical events which results in irreversible neuronal damage in cerebral ischemia. The effect of the NMDA antagonist upon the amount of ischemic brain damage has been already assessed by some investigators. But most of them were performed only in acute ischemic models. In the light of clinical experiences, it's neuroprotective effect is much more important in the prolonged ischemic model. So, authors produced the permanent occlusion of the left middle cerebral artery(MCAO) and sacrificed the animals 48 hours after the occlusion to observe the neuroprotective effect of the NMDA antagonist, MK-801, in the maturated condition of ischemia according to the previous PART I experiment. MK-801 was administered 2 times, intravenously 1 hours prior to MCA occlusion(0.5 mg/kg) and intraperitoneally 1 hour after the induction of ischemia(5 mg/kg) to maintain proper concentration of the drug. CBF was measured by hydrogen clearance methods. Areas of brain infarction were delineated by tetrazolium salt at the preselected 8 coronal levels of forebrain and measured on scale diagrams by a plannimeter. MK-801 had no effect on the cardiopulmonary function. In the control, the basal value of CBF was around 118 ml/100 g/min. Immediately after MCAO, CBF of the ipsilateral cortex was reduced to 13.3+/-2.6 ml/100 g/min and not recovered until the end of the experiment. But CBF of the contralateral cortex was maintained in the basal value throughout the experiment. In the treated, immediately after the intravenous administration of the drug. CBF of both frontal cortices was reduced to 15 to 20% of the basal value(P<0.001), and the reduced CBF was noted even after MCAO, comparing to the control, but 24 hours later the reduced CBF of the contralateral cortex recovered to the basal value. Treatment with MK-801 reduced the total amount of ischemic damage in the cerebral hemisphere(15.82+/-2.41 versus 10.66+/-1.33 cm, P<0.001) and the cerebral cortex(11.0+/-3.73 versus 6.30+/-1.6 cm, P<0.001). But the effect on the caudate nucleus was minimal. This experiment provides evidence for the potency of the glutamate antagonist, MK-801, in reducing ischemic brain damage, despite the result was obtained 48hours after MCAO. And the anti-ischemic effect of MK-801 in the experiment could not be attributed to by improvement of blood flow to the hypoperfused cerebral tissue.