Hyperthermia Nullifies the Ameliorating Effect of Dizocilpine Maleate (MK-801) in Focal Cerebral Ischemia

The present study was inspired by two previous findings from the laboratory. The first was that dizocilpine maleate (MK-801) fails to reduce infarct size when the middle cerebral artery (MCA) is permanently occluded by an intraluminal filament technique in rats. In seeking the reasons for this we measured temperature and found that the body temperature of occluded animals increases to 39.0-39.5 degrees C during the first 2-3 h. In order to explore whether the rise in temperature was responsible for the lack of effect of MK-801, two groups of animals were studied, both containing animals which were subjected to 2 h of transient MCA occlusion and given MK-801 15 min before, as well as 6 and 24 h after ischemia. In one group, temperature was allowed to rise spontaneously during ischemia (39.0-39.5 degrees C). In the other, body temperature was maintained close to normal during ischemia, and for the first 6 h postischemically, by cooling of the ambient air. Infarct volume was assessed by triphenyltetrazolium chloride staining after 48 h of recovery. The results showed that MK-801 failed to reduce infarct size in animals whose body temperature rose during ischemia. In contrast, the drug markedly reduced infarct volume in temperature-controlled animals; in fact, 5/8 animals had no infarcts but selective neuronal damage only. The results suggest that amelioration of focal ischemic damage cannot be expected if body and brain temperature is allowed to rise above normal.