Neuroprotection by MK-801 in temperature maintained gerbils

Hypothermia reduces ischemic brain damage, confounding interpretation of the neuroprotective effects of drugs. Specifically, the neuroprotectant MK-801 has been shown to cause hypothermia. Some have claimed that when body temperature is maintained, MK-801 is not a neuroprotectant, whereas others claim it retains its neuroprotective activity. MK-801 was evaluated for neuroprotective properties in free-regulating as well as temperature-maintained gerbils receiving 5 or 10 min of bilateral carotid occlusion. After 10 min of ischemia, free-regulating animals exhibited significant hypothermia (as low as 32 degrees C) and showed significant neuroprotection after 3 mg/kg IP MK-801. When a hyperthermic body temperature (38.5 degrees C) was maintained, no reduction in brain damage was evident after up to 10 mg/kg IP MK-801, even when occlusion time was reduced to 5 min. However, when a normothermic body temperature (36.5 degrees C) was maintained, 10 mg/kg IP MK-801 significantly reduced brain damage after 5 min of ischemia. Thus, although a higher dose of the drug is required, MK-801 can reduce ischemic brain damage in the absence of hypothermia. The need for this high dose suggests that mechanisms other than NMDA receptor complex antagonism may be involved in the neuroprotective actions of MK-801.