Cholecystokinin-related peptides, after systemic or central administration, prevent carbon monoxide-induced amnesia in mice

T. Maurice, M. Hiramatsu, T. Kameyama, T. Hasegawa, T. Nabeshima

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The neuroprotective actions of cholecystokinin (CCK) peptides were investigated in a mouse hypoxia model, in which the animals were successively exposed to CO gas. Working memory impairment 5 days after CO exposure was examined by using a Y-maze test; delayed amnesia was examined 7 days after CO exposure, by using a step-down type passive avoidance test. Ceruletide (1- 100 μg/kg, given s.c. 30 min before CO exposure) significantly prevented the CO-induced impairment of performance in both tests, the improvement being correlated with the severity of hypoxia. This severity was increased by maintaining the body temperature at 38°C. Ceruletide was less effective when injected immediately after a single CO exposure. The order of potency of the CCK-peptides administered systemically was: ceruletide > CCK-8S > CCK-8NS >> CCK-4. Ceruletide (0.03-0.3 μg/mouse) and CCK-8S (0.03-1 μg/mouse) prevented CO-induced amnesia after i.c.v. administration. Under all experimental conditions, dizocilpine [MK-801, (+)-5-methyl-10,11-dihydro-5H- dibenzo(a,d)cyclohepten-5,10-imine maleate, 500 μg/kg s.c. or 10 μg/mouse i.c.v.] prevented completely the CO-induced amnesia. The protective effects of systemic ceruletide were blocked, partially but significantly, by the preadministration of L-364,718 {3S-(-)-N-[2,3-dihydro-1-methyl-2-oxo-S- phenyl-1H-1,4-benzodiazepine-3-yl]-1H-indole-2-carboxamide, 1-10 mg/kg i.p.}, a selective CCK-A receptor antagonist. L-365,260 {[3R-(+)-2,3- dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl]-N'-[3-methyl- phenyl]urea}, a CCK-B antagonist, also decreased ceruletide-induced protection. The effect of centrally administered ceruletide was blocked selectively and completely by L-365,260 (1-10 mg/kg i.p.). These results indicate that CCK peptides have neuroprotective properties in CO-induced amnesia, a condition which may involve glutamate excitotoxicity. Two different mechanisms appeared to be responsible for the protective action of ceruletide, a systemic mechanism, operating through CCK-A receptors, and a centrally acting mechanism, operating through CCK-B receptors.

Original languageEnglish
Pages (from-to)665-673
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
Publication statusPublished - 01-01-1994
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology


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