Pharmacological actions of a new TRH analogue, YM-14673, in rats subjected to cerebral ischemia and anoxia.

The cerebral protective actions of a new thyrotropin releasing hormone (TRH) analogue, YM-14673, [Na-[[(S)-4-oxo-2-azetidinyl-carbonyl]-L-histidyl-L-prolinamide] dihydrate), were compared with those of CDP-choline (cerebral metabolic enhancer) and naloxone in rats rats subjected to unilateral carotid artery ligation and anoxic exposure (Levine rats). Drugs were administered intraperitoneally or orally 20, 80, and 140 min after anoxia. YM-14673 (0.03 to 1 mg/kg i.p. and 0.3 to 10 mg/kg p.o.) decreased the incidence of neurological deficits, such as hemiplegia and convulsion followed by coma and death, for 48 h after ischemia and anoxia. Both the increase in the brain water content and the degeneration of neurons in the cerebral cortex and thalamus were prevented by YM-14673 at a dose of 0.1 mg/kg (i.p.). CDP-choline (400 mg/kg i.p.), which is currently used in the therapy of cerebral vascular diseases, and naloxone (3 mg/kg i.p.) also decreased the incidence of the neurological deficits. These results suggest that YM-14673 protects Levine rats against neurological deficits, presumably by attenuating the development of brain edema and preventing neuronal damage. This compound may be useful in the therapeutic treatment of cerebral vascular diseases.