Sharp F R, Jasper P, Hall J, Noble L, Sagar S M
Department of Neurology, University of California, San Francisco.
Ann Neurol. 1991 Dec;30(6):801-9. doi: 10.1002/ana.410300609.
MK-801 and ketamine are noncompetitive N-methyl-D-aspartate (NMDA) receptor blockers that decrease brain injury in animal models of focal and global ischemia. Recent reports, however, suggested that MK-801 itself can damage neurons. Here we show that MK-801 (0.1 to 5.0 mg/kg) and ketamine (40 to 100 mg/kg) typically induce heat shock protein HSP72 mainly in layer 3 neurons of the posterior cingulate and retrosplenial cortex of the rat. These HSP72-immunoreactive neurons contain abnormal cytoplasmic vacuoles visualized by electron microscopy. The HSP72 immunoreactivity is maximal at 24 hours with 1.0-mg/kg doses of MK-801 and disappears by 2 weeks. Based on these data, we propose: (1) MK-801 and ketamine injure selected neurons, which express HSP72 in response to that injury. (2) Since HSP72 is induced for 1 to 2 weeks, the prolonged psychological side effects of MK-801, ketamine, phencyclidine, and related drugs could be related to this injury. (3) The neuroprotective effect of MK-801 is probably not related to HSP72 induction. (4) HSP72 immunocytochemistry is useful for studying nonlethal neuronal injury from a wide variety of brain insults.
MK-801和氯胺酮是非竞争性N-甲基-D-天冬氨酸（NMDA）受体阻滞剂，可减轻局灶性和全脑缺血动物模型中的脑损伤。然而，最近的报告表明，MK-801本身可损伤神经元。在此我们表明，MK-801（0.1至5.0毫克/千克）和氯胺酮（40至100毫克/千克）通常主要在大鼠后扣带回和压后皮质第3层神经元中诱导热休克蛋白HSP72。这些HSP72免疫反应性神经元含有通过电子显微镜观察到的异常胞质空泡。1.0毫克/千克剂量的MK-801在24小时时HSP72免疫反应性最强，2周后消失。基于这些数据，我们提出：（1）MK-801和氯胺酮损伤特定神经元，这些神经元会因该损伤而表达HSP72。（2）由于HSP72诱导持续1至2周，MK-801、氯胺酮、苯环利定及相关药物长期的心理副作用可能与此损伤有关。（3）MK-801的神经保护作用可能与HSP72诱导无关。（4）HSP72免疫细胞化学对于研究各种脑损伤引起的非致死性神经元损伤很有用。
