Tamura Y, Sato Y, Akaike A, Shiomi H
2nd Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Japan.
Brain Res. 1992 Oct 2;592(1-2):317-25. doi: 10.1016/0006-8993(92)91691-7.
The protective effects of cholecystokinin (CCK) against glutamate-induced cytotoxicity were examined using cultured neurons obtained from the rat cerebral cortex. Cell viability was significantly reduced when the cultures were briefly exposed to glutamate or N-methyl-D-aspartate (NMDA) and then incubated with normal medium for 60 min. A 60-min exposure to kainate also reduced cell viability. CCK protected cortical neurons against glutamate-, NMDA- and kainate-induced cytotoxicity. Glutamate- and NMDA-induced cytotoxicity was also reduced by N omega-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor. However, CCK did not prevent the cytotoxic effects of sodium nitroprusside (SNP) which spontaneously releases NO. Moreover, CCK did not affect NMDA-induced Ca2+ influx measured with rhod-2, a fluorescent Ca2+ indicator. Therefore, release of a NO-like factor from the cerebral cortex was assayed using the thoracic artery in vitro. When the artery was incubated with minced cerebral tissues, glutamate elicited marked relaxation. SNP also elicited relaxation of the smooth muscle. CCK inhibited glutamate-induced relaxation but did not affect that induced by SNP. These results indicate that CCK prevents NMDA receptor-mediated cytotoxicity without reducing the Ca2+ influx. It is suggested that CCK inhibits NO-formation triggered by NMDA receptor activation.
利用从大鼠大脑皮层获取的原代培养神经元，研究了胆囊收缩素（CCK）对谷氨酸诱导的细胞毒性的保护作用。当培养物短暂暴露于谷氨酸或N-甲基-D-天冬氨酸（NMDA），然后在正常培养基中孵育60分钟时，细胞活力显著降低。暴露于红藻氨酸60分钟也会降低细胞活力。CCK可保护皮层神经元免受谷氨酸、NMDA和红藻氨酸诱导的细胞毒性。一氧化氮（NO）合酶抑制剂Nω-硝基-L-精氨酸也可降低谷氨酸和NMDA诱导的细胞毒性。然而，CCK并不能阻止自发释放NO的硝普钠（SNP）的细胞毒性作用。此外，CCK不影响用荧光Ca2+指示剂rhod-2测量的NMDA诱导的Ca2+内流。因此，使用离体胸主动脉检测大脑皮层中类NO因子的释放。当主动脉与切碎的脑组织一起孵育时，谷氨酸引起明显的舒张。SNP也引起平滑肌舒张。CCK抑制谷氨酸诱导的舒张，但不影响SNP诱导的舒张。这些结果表明，CCK可预防NMDA受体介导的细胞毒性，而不减少Ca2+内流。提示CCK抑制NMDA受体激活触发的NO生成。
