ceruletide and Amnesia

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 micrograms/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 degrees 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 micrograms/mouse) and CCK-8S (0.03-1 microgram/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 micrograms/kg s.c. or 10 micrograms/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.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amnesia; Animals; Avoidance Learning; Carbon Monoxide; Ceruletide; Disease Models, Animal; Injections, Intraventricular; Male; Mice; Sincalide

The neuroprotective action of a cholecystokinin octapeptide analogue, ceruletide, was evaluated in models of cerebral ischemia using Mongolian gerbils. Ceruletide significantly suppressed the hyperactivity and amnesia induced by ischemia when injected s.c. 30 min before 5-min occlusion of the bilateral common carotid arteries at room temperature or immediately after their reperfusion. Ceruletide also reduced behavioral changes in ischemic gerbils whose body temperature was maintained at 37 degrees C during the 3-min occlusion. In these groups, delayed neuronal cell death in the hippocampal CA1 area following ischemia was markedly attenuated by s.c. administration of ceruletide. On the other hand, ceruletide could not inhibit the behavioral changes or the neurodegeneration induced in the hippocampal CA1 area by 5-min occlusion at 37 degrees C. These findings indicate that peripheral injection of ceruletide produces a neuroprotective action against moderate cerebral ischemia, which is the first evidence suggesting the efficacy of ceruletide in neurodegenerative diseases.

Topics: Amnesia; Animals; Body Temperature; Brain; Brain Ischemia; Ceruletide; Gerbillinae; Hippocampus; Injections, Subcutaneous; Male; Motor Activity; Nerve Degeneration

It has been established in experiments on male mice and rats that caerulein antagonized the behavioural effects of ketamine, an agonist of phencyclidine receptors. Caerulein (75-375 micrograms/kg) and haloperidol (0.1-1.5 mg/kg) suppressed the stereotyped behaviour and motor excitation induced by ketamine (30 mg/kg) in mice. Caerulein and haloperidol failed to affect ketamine-induced ataxia. Caerulein (10 micrograms/kg) and the opioid antagonist naloxone (5 mg/kg) completely blocked the amnestic action of ketamine (30 mg/kg) in passive avoidance experiments on rats. It seems likely that the suppression of the behavioural effects of ketamine by caerulein is related to its functional antagonism with dopamine and opioid receptors.

Topics: Amnesia; Animals; Ataxia; Behavior, Animal; Ceruletide; Haloperidol; Ketamine; Male; Mice; Motor Activity; Naloxone; Rats; Receptors, Cholecystokinin; Stereotyped Behavior