Effects of YM-14673, a new TRH analogue, on behavioral and electrophysiological changes in rats subjected to electrical lesion of the internal capsule.
The effects of YM-14673, a new thyrotropin-releasing hormone (TRH) derivative (N alpha-[[(S)-4-oxo-2-azetidinyl]carbonyl]- L-histidyl-L-prolinamide dihydrate), on the pyramidal motor system were studied in comparison with those of TRH in rats subjected to electrical destruction of the left internal capsule, a brain region of the pyramidal motor tract. In this model, neurological deficits such as hemiplegia and decrease of amplitude of electromyographic activity evoked by electrical stimulation of the left sensory motor cortex, were observed on the right legs. Drug administrations were started from 1 day after the surgical operation on and conducted once or several times a day for 13 days. YM-14673 (0.1 mg/kg, i.p., i.v., i.m.; 1 mg/kg, p.o.), unlike its metabolite (M-1) (10 mg/kg, i.p.), accelerated the recovery from neurological deficits. Decrease of evoked EMG activity on the 6th day after surgery was improved by administration of YM-14673 (0.1 mg/kg, i.p.). Intraperitoneal administration of TRH (1-10 mg/kg) once a day did not show any influence on neurological deficits. However, multiple i.p. administrations of TRH seven times in 1 hr accelerated recovery from deficits. These TRH activities are supported by metabolic studies which indicated that a high plasma level of TRH was maintained by multiple administrations of TRH. These results suggest that YM-14673 has a facilitatory effect on the pyramidal motor system which is due, in part, to its TRH-like properties.
Yamamoto
M
M
Central Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Shimizu-Sasamata
M
M
Kawabata
S
S
Terai
M
M
D000818:Animals; D001384:Azetidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D002545:Brain Ischemia / Q000503:physiopathology; D004151:Dipeptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004558:Electric Stimulation; D004576:Electromyography; D004594:Electrophysiology; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D009046:Motor Neurons / Q000187:drug effects; D009422:Nervous System Diseases / Q000139:chemically induced / Q000503:physiopathology; D011712:Pyramidal Tracts / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology
D001384:Azetidines; D004151:Dipeptides; D013973:Thyrotropin-Releasing Hormone; C054995:azetirelin