Sharp J W
Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan 66506, USA.
Brain Res. 1996 Jul 29;728(2):215-24. doi: 10.1016/0006-8993(96)00411-8.
The physiological model for glutamate receptor mediated excitotoxicity entails elevation of intraneuronal calcium levels. Excessive activation of the NMDA receptor leads to excitotoxicity by prolonged calcium influx via its calcium channel. The purpose of this research was to examine the mechanism of non-NMDA glutamate receptor mediated excitotoxicity. Mammalian AMPA receptors do not show significant calcium conductance. However, some kainate receptors show significant calcium conductance. The hypothesis of this research states that non-NMDA glutamate agonists (quisqualate (5 microliters of 2 mg/ml i.c.v.), AMPA (4 microliters of 1 mg/ml i.c.v.), and kainate (15 mg/kg i.p.)) produce significant heat shock gene, hsp70, induction via glutamate release with subsequent opening of the NMDA receptor calcium channel. PCP (phencyclidine) and ketamine are noncompetitive blockers of the NMDA calcium channel. They act to prevent significant NMDA receptor excitotoxicity. PCP (20 mg/kg i.p.) and ketamine (60 mg/kg i.p.) both diminished quisqualate and AMPA hsp70 induction in the CA1, CA2, CA3 areas of the hippocampus, in the polymorph area of the dentate gyrus, and in the parietal neocortex. PCP significantly (P < 0.05) diminished kainate hsp70 induction only in the CA1 area and the neocortex. Ketamine failed to reduce kainate hsp70 induction. AMPA receptors appear to result in excitotoxic damage via glutamate release. Glutamate opens NMDA receptor calcium channels which increases intraneuronal calcium levels. Kainate receptors probably mediate excitotoxicity via direct calcium conductance with glutamate release being important in the CA1 area and neocortex.
谷氨酸受体介导的兴奋毒性的生理模型涉及神经元内钙水平的升高。NMDA受体的过度激活通过其钙通道导致钙的持续内流，从而引发兴奋毒性。本研究的目的是探讨非NMDA谷氨酸受体介导的兴奋毒性机制。哺乳动物的AMPA受体不显示明显的钙传导。然而，一些海人藻酸受体显示出明显的钙传导。本研究的假设是，非NMDA谷氨酸激动剂（quisqualate（脑室内注射2 mg/ml的5微升）、AMPA（脑室内注射1 mg/ml的4微升）和海人藻酸（腹腔注射15 mg/kg））通过谷氨酸释放，随后打开NMDA受体钙通道，从而显著诱导热休克基因hsp70。PCP（苯环己哌啶）和氯胺酮是非竞争性的NMDA钙通道阻滞剂。它们的作用是防止明显的NMDA受体兴奋毒性。PCP（腹腔注射20 mg/kg）和氯胺酮（腹腔注射60 mg/kg）均减少了海马体CA1、CA2、CA3区域、齿状回多形层以及顶叶新皮质中quisqualate和AMPA诱导的hsp70。PCP仅在CA1区域和新皮质中显著（P<0.05）减少了海人藻酸诱导的hsp70。氯胺酮未能降低海人藻酸诱导的hsp70。AMPA受体似乎通过谷氨酸释放导致兴奋毒性损伤。谷氨酸打开NMDA受体钙通道，从而增加神经元内钙水平。海人藻酸受体可能通过直接钙传导介导兴奋毒性，而谷氨酸释放在CA1区域和新皮质中很重要。
