Mechanisms of cholecystokinin-induced protection of cultured cortical neurons against N-methyl-D-aspartate receptor-mediated glutamate cytotoxicity.
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.
2nd Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Japan.
Y
Y
Tamura
Y
Y
Sato
A
A
Akaike
H
H
Shiomi
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D002108:Ceruletide / Q000494:pharmacology; D002766:Cholecystokinin / Q000494:pharmacology*; D005971:Glutamates / Q000494:pharmacology*; D018698:Glutamic Acid; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
D000596:Amino Acids; D005971:Glutamates; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D018698:Glutamic Acid; D002108:Ceruletide; D002766:Cholecystokinin; D002118:Calcium