Shinohara S, Katsuura G, Eigyo M, Shintaku H, Ibii N, Matsushita A
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Brain Res. 1992 Aug 21;588(2):223-8. doi: 10.1016/0006-8993(92)91579-4.
To study the mechanism by which cholecystokinin octapeptide (CCK-8) and its potent analogue, ceruletide, prevent glutamate-induced neuronal cell death in rat neuron cultures, we examined the effect of both peptides on glutamate-induced increases in the intracellular free calcium concentrations ([Ca2+]i), which are known to be a crucial trigger of the neurodegeneration induced by glutamate. CCK-8 itself did not alter [Ca2+]i in rat neuron cultures. Glutamate increased [Ca2+]i in neuron cultures rapidly and markedly. CCK-8 and ceruletide significantly suppressed the increases in [Ca2+]i induced by glutamate. The maximum inhibitory effects of CCK-8 and ceruletide at 10(-6) M reached 43 and 46% of the response to glutamate, respectively. Gastrin-I and CCK-4 also significantly attenuated the increases in [Ca2+]i induced by glutamate. The inhibitory effect of CCK-8 was completely blocked by the selective antagonist for CCK-B receptors, (+)L-365,260, but not by (-)L-364,718, which is a selective antagonist for CCK-A receptors. CCK-8 significantly suppressed [Ca2+]i response to kainate and high concentrations of extracellular K+, but not to N-methyl-D-aspartate. With cultured astrocytes, CCK-8 did not inhibit the increment of [Ca2+]i induced by glutamate. These findings clearly demonstrated that CCK-8 and ceruletide inhibit glutamate-induced increases in [Ca2+]i in neuron cultures through CCK-B receptors, suggesting that CCK-8 may participate in the central actions of glutamate.
为研究八肽胆囊收缩素（CCK-8）及其强效类似物蛙皮素在大鼠神经元培养物中预防谷氨酸诱导的神经元细胞死亡的机制，我们检测了这两种肽对谷氨酸诱导的细胞内游离钙浓度（[Ca2+]i）升高的影响，已知细胞内游离钙浓度升高是谷氨酸诱导神经变性的关键触发因素。CCK-8本身不会改变大鼠神经元培养物中的[Ca2+]i。谷氨酸能迅速且显著地升高神经元培养物中的[Ca2+]i。CCK-8和蛙皮素能显著抑制谷氨酸诱导的[Ca2+]i升高。10(-6)M的CCK-8和蛙皮素的最大抑制作用分别达到对谷氨酸反应的43%和46%。胃泌素-I和CCK-4也能显著减弱谷氨酸诱导的[Ca2+]i升高。CCK-8的抑制作用被CCK-B受体的选择性拮抗剂(+)L-365,260完全阻断，但不被CCK-A受体的选择性拮抗剂(-)L-364,718阻断。CCK-8能显著抑制对海人酸和高浓度细胞外钾的[Ca2+]i反应，但对N-甲基-D-天冬氨酸无抑制作用。对于培养的星形胶质细胞，CCK-8不抑制谷氨酸诱导的[Ca2+]i升高。这些发现清楚地表明，CCK-8和蛙皮素通过CCK-B受体抑制神经元培养物中谷氨酸诱导的[Ca2+]i升高，提示CCK-8可能参与谷氨酸的中枢作用。
