Inhibitory effect of CCK-8 and ceruletide on glutamate-induced rises in intracellular free calcium concentrations in rat neuron cultures.
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.
Shinohara
S
S
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Katsuura
G
G
Eigyo
M
M
Shintaku
H
H
Ibii
N
N
Matsushita
A
A
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002108:Ceruletide / Q000494:pharmacology*; D002766:Cholecystokinin / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology; D005260:Female; D016257:Fura-2; D005971:Glutamates / Q000494:pharmacology*; D018698:Glutamic Acid; D007608:Kainic Acid / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D011949:Receptors, Cholecystokinin / Q000187:drug effects
D005971:Glutamates; D011949:Receptors, Cholecystokinin; D003561:Cytarabine; D018698:Glutamic Acid; D016202:N-Methylaspartate; D002108:Ceruletide; D002766:Cholecystokinin; D007608:Kainic Acid; D002118:Calcium; D016257:Fura-2