Hoffman C A, Boast C A
Wyeth-Ayerst Research, Princeton, NJ 08543, USA.
Brain Res Bull. 1995;38(4):405-9. doi: 10.1016/0361-9230(95)02008-f.
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.
体温过低会减轻缺血性脑损伤，这使得对药物神经保护作用的解读变得复杂。具体而言，神经保护剂MK-801已被证明会导致体温过低。一些人声称，当维持体温时，MK-801不是神经保护剂，而另一些人则声称它保留了神经保护活性。在自由调节体温以及维持体温的沙土鼠中，对MK-801的神经保护特性进行了评估，这些沙土鼠接受了5或10分钟的双侧颈动脉闭塞。缺血10分钟后，自由调节体温的动物出现明显的体温过低（低至32摄氏度），在腹腔注射3mg/kg MK-801后显示出明显的神经保护作用。当维持高热体温（38.5摄氏度）时，即使将闭塞时间缩短至5分钟，腹腔注射高达10mg/kg的MK-801后，脑损伤也没有明显减轻。然而，当维持正常体温（36.5摄氏度）时，腹腔注射10mg/kg的MK-801在缺血5分钟后能显著减轻脑损伤。因此，尽管需要更高剂量的药物，但在没有体温过低的情况下，MK-801可以减轻缺血性脑损伤。对这种高剂量的需求表明，除了NMDA受体复合物拮抗作用之外的其他机制可能参与了MK-801的神经保护作用。
