Panegyres P K
Department of Neuropathology, Royal Perth Hospital, Western Australia.
J Neural Transm (Vienna). 1998;105(4-5):463-78. doi: 10.1007/s007020050070.
This work has explored the relationship between excitotoxicity and the amyloid precursor protein gene (APP) which may be relevant to future therapeutic developments in Alzheimer's disease. The excitotoxic effects of kainic acid (KA) and pentylenetetrazole (PTZ) have been compared and contrasted on the two major mRNA isoforms of APP using in situ hybridization and quantitative analysis of gene expression in rat brain. The Kunitz Protease Inhibitor containing isoform APP 770 KPI+, the major glial cell isoform, has been shown to be stimulated after KA and was related to neuronal loss and astrocyte activation as gauged by GFAP mRNA. This was associated with reduced expression of APP695 KPI- isoform, the major neuronal isoform. These changes were not observed after PTZ where there was no neuronal loss and no glial reaction. The KA induced changes in APP were prevented by pretreatment with the non-competitive NMDA receptor antagonist dizocilpine and the barbiturate pentobarbitone, but not with the kappa-opioid receptor agonist enadoline. These findings were related to the suppression of seizures and the survival of neurons. In conclusion, excitotoxic stimulation leading to neuronal death was associated with increased expression of APP KPI+ mRNA and decreased APP KPI- mRNA, a finding which may relate to the plasticity of the central nervous system.
这项研究探讨了兴奋性毒性与淀粉样前体蛋白基因（APP）之间的关系，这可能与阿尔茨海默病未来的治疗进展相关。使用原位杂交和大鼠脑内基因表达的定量分析，对比了红藻氨酸（KA）和戊四氮（PTZ）对APP的两种主要mRNA异构体的兴奋性毒性作用。含库尼茨蛋白酶抑制剂的APP 770 KPI +异构体是主要的神经胶质细胞异构体，已证实在KA作用后其受到刺激，并且与神经元损失和由GFAP mRNA测定的星形胶质细胞活化有关。这与主要神经元异构体APP695 KPI - 异构体的表达降低有关。在PTZ作用后未观察到这些变化，PTZ作用后没有神经元损失和神经胶质反应。KA诱导的APP变化可通过非竞争性NMDA受体拮抗剂地佐环平及巴比妥类药物戊巴比妥预处理来预防，但κ-阿片受体激动剂依那朵林则不能。这些发现与癫痫发作的抑制和神经元的存活有关。总之，导致神经元死亡的兴奋性毒性刺激与APP KPI + mRNA表达增加和APP KPI - mRNA表达降低有关，这一发现可能与中枢神经系统的可塑性有关。
