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Involvement of calcium ion in apoptosis induced by NMDA antagonists and ethanol

钙离子参与NMDA拮抗剂和乙醇诱导的细胞凋亡

基本信息

批准号：
11672195
负责人：
TAKADERA Tsuneo
金额：
$ 1.54万
依托单位：
Hokuriku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672195/
关键词：
NMDA receptor calcium ion apoptosis caspase MK-801 ifenprodil ethanol 大脳皮質細胞カスパーゼ3

项目摘要

The NMDA receptor and receptor-associated ion channel are assumed to play a principal role in glutamate excitotoxicity on neurons of the cortex and hippocampus. NMDA antagonists (NK801, APV) and ethanol inhibit the NMDA neurotoxicity in cultured cortical neurons. However, NMDA antagonists and ethanol are known to be toxic to certain neuronal populations. In the present study, we have examined whether NMDA antagonists and ethanol induce neuronal apoptosis in a culture condition. Exposure of rat cortical cultures (10 days in vitro) to MK801 (1 nM to 10 μM ) and ethanol (50 to 300 mM) for 24 to 48 hr resulted in apoptotic cell death in a dose-dependent manner. NMDA (25 and 50 μM) attenuated the MK801-and ethanol-induced cell death. MK801 and ethanol decreased intracellular calcium ion concentrations. Activation of caspase-3 was accompanied by MK801-and ethanol-induced cell death in a dose-dependent manner. Further, cycloheximide (0.1 and 0.2 μg/ml) protected the cells from MK801 and ethanol-induced cell death and caspase-3 activation. Insulin-like growth factor 1 (5 to 20 ng/ml) also inhibited the cell death and caspase-3 activation induced by MK801 and ethanol. Ifenprodil, a NR2B-selective NMDA antagonist, also induced apoptotic cell death and caspase-3 activation. These results indicate that the moderate NMDA receptor activation may support the survival of neurons during the neuronal development, and drugs which inhibit NMDA receptor may induce apoptosis.

NMDA受体和受体相关离子通道被认为在谷氨酸对大脑皮层和海马神经元的兴奋性毒性中起主要作用。NMDA拮抗剂(NK801、APV)和乙醇可抑制培养的大脑皮层神经元的NMDA神经毒性。然而，已知NMDA拮抗剂和乙醇对某些神经元群体有毒性。在本研究中，我们研究了NMDA拮抗剂和乙醇在培养条件下是否诱导神经细胞凋亡。体外培养的大鼠皮质细胞在MK801(1 NM~10μM)和乙醇(50~300 mM)作用24~48小时后，细胞发生凋亡，并呈剂量依赖性。N-甲基-D-天冬氨酸(25和50μM)可减轻MK801和乙醇诱导的细胞死亡。MK801和乙醇降低细胞内钙离子浓度。Caspase-3的激活伴随着MK801和乙醇诱导的细胞死亡，并呈剂量依赖关系。放线菌酮(0.1和0.2μg/ml)对MK80 1和乙醇诱导的细胞死亡和半胱氨酸天冬氨酸氨基转移酶3的激活有保护作用。胰岛素样生长因子1(5~20 ng/ml)也可抑制MK801和乙醇诱导的细胞死亡和caspase-3的激活。NR2B选择性NMDA拮抗剂ifenprodil也可诱导细胞凋亡和caspase-3激活。这些结果表明，在神经元发育过程中，适度的NMDA受体激活可能支持神经元的存活，抑制NMDA受体的药物可能会诱导细胞凋亡。