Pharmacological study of the temporary cerebral ischemic rats produced by bilateral vertebral and carotid artery occlusion. Effects of DN-1417.

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Abstract
The ameliorating effects of DN-1417 [.alpha.-butyrolactone-.gamma.-carbonyl-L-histidyl-L-prolinamide citrate] (a TRH analog) were investigated on the changes of behavior, EEG, neurochemical parameters and regional cerebral blood flow (rCBF) in rats with global cerebral ischemia. Global cerebral ischemia was produced by 10 min occlusion of both common carotid arteries 24 h after the permanent electrocauterization of bilateral vertebral arteries. DN-1417 was administered i.p. as soon as possible, following recirculation of carotid blood flow. DN-1417 shortened signficantly the recovery times of righting reflex (RR) and spontaneous movement (SM) at 2.5 mg/kg and higher doses, and it recovered effectively the EEG activity at 10 mg/kg during recirculation after 10 min cerebral ischemia. DN-1417 (10 mg/kg) recovered the various changes such as decrease of 5-hydroxytryptamine (5-HT) levels, increase of cAMP levels, inhibition of [3H]-choline uptake, depression of choline acetyltransferase (CAT) and acetylcholine esterase (AChE) activities, and shortened the durations of hyperfusion and hypoperfusion of rCBF. DN-1417 ameliorates the disturbances of consciousness supposedly caused by behavioral and EEG abnormalities during recirculation following the temporary cerebral ischemia, and the effect of DN-1417 seems to be mediated by normalizing of alterations in the brain monoaminergic and cholinergic systems, as well as rCBF, and the effectiveness for disturbance of consciousness in clinical situations would be expected.