Wilson M A, Kinsman S L, Johnston M V
Department of Neuroscience, Kennedy Krieger Research Institute, 707 N. Broadway, Baltimore, MD 21205, USA.
Brain Res Dev Brain Res. 1998 Aug 8;109(2):211-20. doi: 10.1016/s0165-3806(98)00084-4.
Although NMDA receptor antagonists are neuroprotective when delivered in conjunction with NMDA, supersensitivity to NMDA-mediated injury follows dizocilpine (MK-801) administration in neonatal rats. An increase in NMDA-sensitive [3H]-glutamate binding accompanies the increase in vulnerability to excitotoxic injury. The present study tests the hypothesis that MK-801 may alter gene expression for the NMDA receptor subunits. Quantitative in situ hybridization histochemistry was used to evaluate the expression of NMDA receptor subunits NR1 and NR2A-D in neonatal rats, 2 to 4 h after treatment with MK-801. Increased mRNA for multiple NMDA receptor subunits was observed in cerebral cortex, striatum and hippocampus. The percent increase in NR2A mRNA was larger than the percent change in NR1, NR2B or NR2D. A small increase in mRNA for the metabotropic glutamate receptor mGluR5 was also observed after MK-801 treatment. These results indicate that gene expression for NMDA receptor subunits in the developing brain is rapidly altered after antagonist exposure. Increased expression of excitatory amino acid receptor subunit mRNA may contribute to the enhanced vulnerability to excitotoxic injury that has been observed after MK-801 treatment.
尽管NMDA受体拮抗剂与NMDA一起给药时具有神经保护作用，但新生大鼠给予地佐环平（MK-801）后会出现对NMDA介导损伤的超敏反应。对兴奋性毒性损伤易感性的增加伴随着NMDA敏感性[3H] -谷氨酸结合的增加。本研究检验了MK-801可能改变NMDA受体亚基基因表达的假说。在新生大鼠用MK-801治疗后2至4小时，采用定量原位杂交组织化学方法评估NMDA受体亚基NR1和NR2A-D的表达。在大脑皮层、纹状体和海马中观察到多个NMDA受体亚基的mRNA增加。NR2A mRNA的增加百分比大于NR1、NR2B或NR2D的变化百分比。MK-801治疗后还观察到代谢型谷氨酸受体mGluR5的mRNA有小幅增加。这些结果表明，发育中大脑中NMDA受体亚基的基因表达在拮抗剂暴露后迅速改变。兴奋性氨基酸受体亚基mRNA表达的增加可能导致了MK-801治疗后观察到的对兴奋性毒性损伤易感性增强。
