Näkki R, Koistinaho J, Sharp F R, Sagar S M
Department of Neurology, University of California, San Francisco 94121.
J Neurosci. 1995 Mar;15(3 Pt 2):2097-108. doi: 10.1523/JNEUROSCI.15-03-02097.1995.
Phencyclidine (PCP), dizocilpine maleate (MK801), and other NMDA antagonists are toxic to neurons in the posterior cingulate and retrosplenial cortex. To determine if additional neurons are damaged, the distribution of microglial activation and 70 kDa heat shock protein (HSP70) induction was studied following the administration of PCP and MK801 to rats. PCP (10-50 mg/kg) induced microglial activation and neuronal HSP70 mRNA and protein expression in the posterior cingulate and retrosplenial cortex. In addition, coronal sections of the cerebellar vermis of PCP (50 mg/kg) treated rats contained vertical stripes of activated microglial in the molecular layer. In the sagittal plane, the microglial activation occurred in irregularly shaped patches, suggesting damage to Purkinje cells. In accord with this finding, PCP induced HSP70 protein and mRNA expression in Purkinje cells. Although there were relatively few foci of microglial activation and cells with HSP70 protein induction, HSP70 mRNA was detected in many Purkinje cells located throughout the cerebellar hemispheres as well as the vermis. MK801, at doses of 5-10 mg/kg, induced microglial activation and neuronal HSP70 mRNA and protein expression in the cingulate and retrosplenial cortex but not in the cerebellum. At the dose of 1 mg/kg MK801 induced HSP70 but did not consistently activate microglia. These data suggest that microglia are activated by MK801 doses that kill or severely damage neurons, whereas HSP70 is induced in "stressed" neurons at MK801 doses well below those that produce severe neurotoxicity. These observations suggest that PCP, but not MK801, is toxic to Purkinje cells and raise the question of whether NMDA antagonists or sigma ligands other than PCP are toxic to the cerebellum. Moreover, this study illustrates the usefulness of microglial activation and HSP70 induction as markers of neurotoxicity.
苯环利定（PCP）、马来酸二氮卓西平（MK801）及其他N-甲基-D-天冬氨酸（NMDA）拮抗剂对后扣带回和压后皮质中的神经元有毒性作用。为了确定是否有更多神经元受损，研究了给大鼠注射PCP和MK801后小胶质细胞激活的分布情况以及70 kDa热休克蛋白（HSP70）的诱导情况。PCP（10 - 50毫克/千克）可诱导后扣带回和压后皮质中的小胶质细胞激活以及神经元HSP70 mRNA和蛋白表达。此外，接受PCP（50毫克/千克）治疗的大鼠的小脑蚓部冠状切片在分子层中含有垂直排列的激活小胶质细胞条纹。在矢状面上，小胶质细胞激活出现在形状不规则的斑块中，提示浦肯野细胞受损。与此发现一致的是，PCP可诱导浦肯野细胞中HSP70蛋白和mRNA表达。虽然小胶质细胞激活灶和诱导出HSP70蛋白的细胞相对较少，但在整个小脑半球以及蚓部的许多浦肯野细胞中都检测到了HSP70 mRNA。剂量为5 - 10毫克/千克的MK801可诱导扣带回和压后皮质中的小胶质细胞激活以及神经元HSP70 mRNA和蛋白表达，但对小脑无此作用。剂量为1毫克/千克的MK801可诱导HSP70，但并未持续激活小胶质细胞。这些数据表明，能杀死或严重损伤神经元的MK801剂量可激活小胶质细胞，而远低于产生严重神经毒性剂量的MK801可在“应激”神经元中诱导HSP70。这些观察结果表明，PCP而非MK801对浦肯野细胞有毒性作用，并提出了除PCP之外的NMDA拮抗剂或西格玛配体是否对小脑有毒性作用的问题。此外，本研究说明了小胶质细胞激活和HSP70诱导作为神经毒性标志物的有用性。
