Antagonizing effects of YM-14673, a new TRH derivative, on behavioral and electroencephalographic changes in reserpinized animals

Yamamoto, Masakazu; Shimizu, Masao; Iwai, Akihiko

doi:10.1007/bf00174502

Cited by 17 publications

(3 citation statements)

References 21 publications

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“…Involvement of central monoaminergic 27 and cholinergic systems 28 is well known in regulating learned behavior. Indeed, YM-14673 as well as TRH possess facilitatory effects on central monoaminergic 29 and cholinergic 30 systems in rodents. Interestingly, there are many reports concerning the antiamnesic activity of TRH in mice.…”

Section: Discussionmentioning

confidence: 99%

Effects of a new thyrotropin-releasing hormone derivative on behavioral changes after focal cerebral ischemia in rats.

Yamamoto¹,

Tamura²,

Kirino³

et al. 1989

Stroke

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We observed the effects of a new thyrotropin-releasing hormone derivative, YM-14673 (A"*-[[(S)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide dihydrate), on behavioral changes in rats for 3 weeks after focal cerebral ischemia. Under halothane anesthesia, the left middle cerebral artery was occluded via a transretro-orbital approach. YM-14673 was administered just after the operation and once a day for 3 weeks. Neurologic deficits, including hemiplegia and abnormal posture, and disturbance of passive avoidance learning were present in solvent-treated control rats for the entire 3 weeks. YM-14673 at 0.1 or 0.3 mg/kg i.p. or 1 mg/ kg p.o. significantly accelerated the recovery of neurologic deficits and ameliorated cognitive disturbance compared with the solvent-treated controls although the drug at 0. 1112 On the other hand, there are only a few reports concerning pathologic and functional changes during the chronic phase of focal cerebral ischemia.11 Therefore, we monitored behavioral changes for 16 weeks after occlusion of the middle cerebral artery (MCA) in rats to investigate functional changes during the chronic phase of this model. 1314 In previous studies we observed neurologic deficits for 4 weeks after MCA occlusion, and learning behavior in a passive avoidance task was disturbed for 8 weeks when the rats were trained 3 days after MCA occlusion. 1314Yasuhara and Naito 15 reported that thyrotropinreleasing hormone (TRH) decreased the threshold for evoked muscular discharge induced by electrical Received June 8, 1988; accepted August 24, 1988. stimulation of the brain reticular formation in rabbits. Yamazaki et al 16 -18 reported that shortening of the latency of a passive avoidance task in rodents subjected to anoxia and treated with cycloheximide or scopolamine was prolonged by administration of TRH. These observations indicate that TRH possesses facilitatory effects on motor function and learned behavior. Recently, Latham et al 19 reported that TRH analogues (RX77368 and CG3509) with long lives prevented the loss of cortical somatosensory evoked potentials in MCA-occluded rats. Therefore, long-acting TRH analogues may show protective action against cerebral ischemia.Since TRH is known to be rapidly metabolized in the body, 20 -21 we have searched for TRH analogues that are more potent and last longer than TRH. (Figure 1), was found to possess analeptic actions such as antagonizing the effects of pentobarbital-induced sleeping time in mice and ameliorating the effects of conscious disturbance in mice with concussions.22 YM-14673 is approximately 10-100 times more potent than TRH in the context of central nervous facilitatory activities. describe the effects of YM-14673 on behavioral changes, including neurologic deficits and disturbance of learned behavior, during 3 weeks following focal cerebral ischemia in rats. Materials and MethodsWe used 67 male Wistar rats, each weighing approximately 300 g, housed in group cages under 12-hour light:dark conditions and given free access to laboratory cho...

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Section: Discussionmentioning

confidence: 99%

Effects of a new thyrotropin-releasing hormone derivative on behavioral changes after focal cerebral ischemia in rats.

Yamamoto¹,

Tamura²,

Kirino³

et al. 1989

Stroke

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“…6 . 7 The aim of our present study is to describe the effects of YM-14673 on neurologic deficits and disturbed learning behavior in rats with MCA occlusion when administered for 2 weeks, beginning 1 week after Received September 13, 1988; accepted February 16, 1989. occlusion. Since numerous complex physiological changes occur during the acute phase of cerebral ischemia, our present experiment was conducted to exclude a drug effect on unrelated factors operating during acute cerebral ischemia.…”

mentioning

confidence: 99%

Effects of a new thyrotropin-releasing hormone analogue administered in rats 1 week after middle cerebral artery occlusion.

Yamamoto¹,

Tamura²,

Kirino³

et al. 1989

Stroke

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T here are a number of drugs, such as cerebral metabolism enhancers or cerebral vasodilators, that are currently used during the chronic phase of cerebral vascular diseases. However, the pharmacologies of these drugs have been evaluated using acute focal cerebral ischemia models. -2 It is of great importance to conduct similar pharmacologic evaluations using a chronic cerebral ischemia model. In previous studies, we observed neurologic deficits and disturbed learning behavior for 4 and 8 weeks after occlusion of the middle cerebral artery (MCA), respectively. 3 -4 Using this model of chronic cerebral ischemia, neurologic deficits and learning behavior disturbances were ameliorated by the administration of YM-14673, a new thyrotropin-releasing hormone (TRH) analoguefor 3 weeks immediately after occlusion. 5 In addition, YM-14673 showed more potent and longer-lasting facilitatory effects on the central nervous system than did TRH. 6 . 7 The aim of our present study is to describe the effects of YM-14673 on neurologic deficits and disturbed learning behavior in rats with MCA occlusion when administered for 2 weeks, beginning 1 week after Received September 13, 1988; accepted February 16, 1989. occlusion. Since numerous complex physiological changes occur during the acute phase of cerebral ischemia, our present experiment was conducted to exclude a drug effect on unrelated factors operating during acute cerebral ischemia. Materials and MethodsWe conducted the studies using 26 male Wistar rats weighing approximately 300 g. The rats were housed in group cages under 12^ 12 hour light:dark conditions and were given free access to laboratory food and water. We anesthetized the 26 rats with 2% halothane and permanently occluded the proximal portion of the left MCA in 20 using a microsurgical technique that was modified from our original method developed by Tamura et al 8 for the purpose of chronic experiments. The stem of the MCA was electrocauterized just medial to the olfactory tract and was cut to ensure the completeness of the vascular occlusion. Six rats received a sham operation.In our previous studies, neurologic deficits in rats subjected to MCA occlusion 5 were ameliorated by the intraperitoneal administration of YM-14673 at doses of 0.1-0.3 and 0.1-1.0 mg/kg. In the present study, we therefore chose a dose of 0.1 mg/kg i.p. YM-14673. The TRH analogue was prepared in our laboratories and dissolved in saline. We began drug (in 10 MCA-occluded rats) or saline (in 10 MCAoccluded and six sham-operated rats) administration 1 week after occlusion and repeated it daily for 2 weeks. Two persons who did not know to which treatment group a rat had been assigned performed the observations. Neurologic deficits were graded

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“…1he Families 01Cognition Enhancers C. SOMATOSTATIN. CHOLECYSTOKININ, NEUROPEPTIDE Y Pharmacopsychiat 22 (1989) 71 HOECHST YM-14 673 (azetirelin) is up to 100 times more potent than TRH itself with regard to arousal effeets ( Yamamoto et al, 1988;Shimizu, 1988b and. The compound is presently -according to Pharmaprojects( I 988b) -in phase III clinical trials in demented patients.…”

Section: B Thyrotropin-releasing Hormone Its Analogues Andprolyl-ementioning

confidence: 99%

The Families of Cognition Enhancers

Fröstl¹,

Maitre²

1989

Pharmacopsychiatry

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An attempt has been made to classify the numerous drugs used to treat cognition deficits according to their chemical structures and to their main physiological effects. Particular emphasis has been given to the following families: Piracetam-type, Co-dergocrine-type and vincamine-type compounds; cholinergic agents, psychostimulants, vasodilators, antianoxic agents, peptides, growth factors and gangliosides. Compounds described in the scientific literature and in patents are presented. Reference has been made to preclinical and clinical studies (973 quotations from original articles, 100 quotations of reviews and books).

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Antagonizing effects of YM-14673, a new TRH derivative, on behavioral and electroencephalographic changes in reserpinized animals

Cited by 17 publications

References 21 publications

Effects of a new thyrotropin-releasing hormone derivative on behavioral changes after focal cerebral ischemia in rats.

Effects of a new thyrotropin-releasing hormone derivative on behavioral changes after focal cerebral ischemia in rats.

Effects of a new thyrotropin-releasing hormone analogue administered in rats 1 week after middle cerebral artery occlusion.

The Families of Cognition Enhancers

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