Minamoto Y, Tanaka T, Shibata S, Watanabe S
Research Laboratory, Yoshitomi Pharmaceutical Industries Ltd., Fukuoka, Japan.
Neurosci Lett. 1994 Feb 14;167(1-2):81-4. doi: 10.1016/0304-3940(94)91032-4.
The effects of cholecystokinin (CCK) receptor agonists and antagonists on hypoxia/hypoglycemia (ischemia)-induced decrease in CA1 presynaptic fiber spikes elicited by the stimulation of Schaffer collaterals were investigated using rat hippocampal slices. Treatment with the CCKB receptor agonist CCK tetrapeptide (CCK4, 0.01-10 microM) exacerbated the ischemia-induced decrease in the CA1 presynaptic potential in a concentration-dependent manner. Whereas, treatment with the CCKB receptor antagonist [(3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4- benzodiazepin-3-yl)-N1-(3-methylphenyl)-urea] (L365260), and not with CCKA receptor antagonist [(3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4- benzodiazepin-3-yl)-1H-indole-2-carboxamide] (L364718), produced a concentration-dependent attenuation of the ischemia-induced decrease. The magnitude of recovery of the CA1 field potentials in L365260-treated groups at 10 and 100 nM was 34% and 45%, respectively. The neuroprotective effect of L365260 (0.01 and 0.1 microM) was completely blocked by co-treatment with CCK4 (0.1 microM), a concentration that did not affect the decreased presynaptic potential induced by ischemia. These results demonstrated that the stimulation of the CCKB receptor played a detrimental role in the development of ischemic damage, whereas the blockade of CCKB receptors played a neuroprotective role in ischemic damage, suggesting a facilitatory role of CCK receptor-operated function in ischemia-induced neuronal deficits.
利用大鼠海马脑片，研究了胆囊收缩素（CCK）受体激动剂和拮抗剂对缺氧/低血糖（缺血）诱导的、由刺激Schaffer侧支所引发的CA1突触前纤维放电减少的影响。用CCK B受体激动剂CCK四肽（CCK4，0.01 - 10微摩尔）处理，以浓度依赖的方式加剧了缺血诱导的CA1突触前电位降低。然而，用CCK B受体拮抗剂[（3R(+)-N-(2,3 - 二氢 - 1 - 甲基 - 2 - 氧代 - 5 - 苯基 - 1H - 1,4 - 苯并二氮杂卓 - 3 - 基）- N1-(3 - 甲基苯基)-脲]（L365260）处理，而非用CCK A受体拮抗剂[（3S(-)-N-(2,3 - 二氢 - 1 - 甲基 - 2 - 氧代 - 5 - 苯基 - 1H - 1,4 - 苯并二氮杂卓 - 3 - 基）- 1H - 吲哚 - 2 - 甲酰胺]（L364718）处理，产生了浓度依赖的对缺血诱导降低的衰减作用。在10和100纳摩尔时，L365260处理组中CA1场电位的恢复幅度分别为34%和45%。L365260（0.01和0.1微摩尔）的神经保护作用被与CCK4（0.1微摩尔）共同处理完全阻断，该浓度并不影响缺血诱导的突触前电位降低。这些结果表明，CCK B受体的激活在缺血性损伤的发展中起有害作用，而CCK B受体的阻断在缺血性损伤中起神经保护作用，提示CCK受体介导的功能在缺血诱导的神经元缺陷中起促进作用。
