Search PubMed⌕ Search

Biomedical subjects

Y Nagawa

Publications and source records attributed to Y Nagawa.

At least 37 records · Page 2Linked to original sources
PubMed1985

In vivo electrochemical detection of 5-hydroxyindoles in the dorsal hippocampus of anesthetized rats treated with idebenone (CV-2619).

The effect of idebenone (CV-2619), 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone, on 5-hydroxyindoles in the dorsal hippocampus of rats was investigated by using in vivo differential pulse voltammetry. CV-2619 (100 mg/kg, i.p.) produced a large increase in oxidation current at 280 mV (peak 2) in the dorsal hippocampus. The increase was statistically significant at 20 and 30 min after the administration. 5-Hydroxytryptophan (150 mg/kg, i.p.) also caused a marked increase in peak 2, which was clearly inhibited by the treatment with pargyline (50 mg/kg, i.p.). Thus, the increase in peak 2 induced by CV-2619 seems to be associated with an increase in the 5-HT metabolite 5-hydroxyindoleacetic acid and also partly with an increase in 5-HT.

5-Hydroxytryptophan↗
PubMed1985

Effects of idebenone (CV-2619) on metabolism of monoamines, especially serotonin, in the brain of normal rats and rats with cerebral ischemia.

The effects of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone, CV-2619) on the contents, turnover, release and uptake of monoamines, especially serotonin (5-HT), in various brain regions of Wistar rats were studied in vivo and in vitro. In normal rats, an intraperitoneal (i.p.) dose of 100 mg/kg of CV-2619 had no significant effect on the levels of norepinephrine (NE), dopamine (DA) and their metabolites, and 5-HT in the brain regions examined, but it increased the levels of 5-hydroxyindole-3-acetic acid (5-HIAA), the main metabolite of 5-HT, in many brain regions. In rats with cerebral ischemia, a low dose (10 mg/kg, i.p.) of CV-2619 normalized the decreased levels of 5-HIAA in the cerebral cortex, hippocampus, diencephalon and brain stem. A 5-HT biosynthesis inhibitor, DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.), decreased the levels of 5-HT in all brain regions to one-third of the control levels 24 hr after administration in normal rats. CV-2619 (10, 30 or 100 mg/kg, i.p.), administered 24 hr after the treatment with PCPA, accelerated the PCPA-induced 5-HT decreases in the hippocampus, diencephalon and brain stem in a dose-dependent manner. In vitro CV-2619, like p-chloroamphetamine (PCA), stimulated 5-HT release from slices of the hippocampus and diencephalon. CV-2619 slightly inhibited and PCA markedly inhibited 5-HT uptake into hippocampal slices. The mechanism of the 5-HT releasing action of CV-2619 in hippocampal slices seems to be mediated through endogenous calcium. These results suggest that CV-2619 has an enhancing effect on the turnover of 5-HT in the hippocampus, diencephalon and brain stem of rats.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

A possible mechanism of action of thyrotropin-releasing hormone (TRH) and its analog DN-1417 on the release of dopamine from the nucleus accumbens and striatum in rats.

Slices of the nucleus accumbens, the terminus of the mesolimbic dopaminergic system and the striatum, the terminus of the nigrostriatal dopaminergic system obtained from rats, were used for analyzing the dopamine releasing effects of TRH and its analog DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate). (1) Dopamine release: The addition of DN-1417 (5 X 10(-5) M) or TRH (5 X 10(-4) M) stimulated the release of prelabelled [3H]-dopamine (DA) from the superfused nucleus accumbens slices, and 100 or 20 times higher concentrations of each compound stimulated DA release from the striatal slices. The omission of Ca2+ from the superfusion medium or the addition of ouabain (5 X 10(-3) M), a (Na+ + K+) stimulated adenosine triphosphate (ATP) phosphohydrolase [(Na+ + K+)-ATPase] inhibitor, almost completely abolished the DN-1417- or TRH-induced DA releasing effect. (2) 45Ca2+ uptake: The addition of DN-1417 (10(-4) M) or TRH (10(-4) M) stimulated 45Ca2+ uptake into the nucleus accumbens slices in a time-dependent manner from 1 to 5 min at 30 degrees C. On the other hand, both drugs (10(-4) M) had no effect on 45Ca2+ uptake into the striatal slices. A Ca2+ ionophore, A-23187 (10(-6) M), stimulated 45Ca2+ uptake into slices of the nucleus accumbens and striatum. Ouabain abolished the DN-1417-, TRH- and A-23187-induced effects. (3) Cyclic AMP formation: The addition of DN-1417 (10(-4) M) or TRH (10(-4) and 10(-3) M) accelerated cyclic AMP formation in the nucleus accumbens, but not in the striatal slices. A Ca2+ antagonist, methoxyverapamil (D-600, 10(-6) M) almost completely abolished the DN-1417- and TRH-effects. (4) (Na+ + K+)-ATPase activity: The addition of DN-1417 (10(-5) and 10(-4) M) or TRH (10(-4) M) activated (Na+ + K+)-ATPase in the P1 fraction (cell debris, nuclei) of the nucleus accumbens, but had little effect on the same activity in the striatum. (5) [3H]-TRH binding: The addition of 10(-6) to 10(-4) M of DN-1417 and TRH inhibited concentration-dependently [3H]-TRH binding in the nucleus accumbens and striatal slices. Ouabain (5 X 10(-3) M) almost completely abolished [3H]-TRH binding in both types of slices.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

[Effect of TRH and its analog DN-1417 on anoxia-induced amnesia in mice].

The effect of neuropeptides and their analogs on anoxia-induced amnesia was examined using one-trial passive avoidance task in mice. Anoxia, produced by the exposure to CO2 immediately after the acquisition of avoidance response, induced amnesia which is shown by a short latency to enter from the safety compartment into the shocked compartment in the retention test conducted 24 hr later. In these anoxia-treated animals, thyrotropin-releasing hormone (TRH: 10-20 mg/kg), its analog DN-1417 (10-20 mg/kg) and ACTH 4-10 (66 micrograms/body), which were given sc 15-60 min before the retention test, markedly prolonged the latency in a dose-dependent manner, indicating a reversal of the amnesia. Arginine- and lysine-vasopressin also reversed the amnesia at a dose of 100 micrograms/body. These results suggest that TRH and DN-1417, known to reverse the amnesia produced by the protein synthesis inhibitor cycloheximide, have ameliorating effects on the retrieval process of memory.

Adrenocorticotropic Hormone↗
PubMed1985

[Effect of idebenone on scopolamine-induced impairment of short-term memory in rats].

The effects of a novel compound, idebenone [6-(10-hydroxydecyl)-2, 3-dimethoxy-5-methyl-1, 4-benzoquinone] and cholinergic drug on short-term memory (STM) were studied in a delayed alternation task in rats. Rats were initially trained using a delayed alternation task in which a forced run to one arm of a T-maze was followed by a free-choice run. A correct free-choice response was defined as a turn toward the arm opposite to that in the forced run, and was rewarded with food pellets. When the time interval between the forced run and free-choice run was longer than 60 sec, the correct responses decreased by about 30% compared with that in no delay trials. After repeated training of the 60 sec-delayed alternation task, the effect of an anticholinergic drug scopolamine (0.1-0.5 mg/kg, ip) on the delayed alternation task was tested. The drug administered 20 min before the test significantly decreased the correct responses in a dose dependent manner. The effect of scopolamine (0.2 mg/kg, ip) was antagonized by the simultaneous administration of physostigmine (0.05-0.2 mg/kg, ip) in a dose dependent manner. Furthermore, physostigmine (0.1 and 0.2 mg/kg, ip) alone increased correct responses in the same task. Idebenone (3-30 mg/kg, ip), administered simultaneously with scopolamine, significantly improved the scopolamine-induced decrement of correct responses, with the highest efficacy at 10 mg/kg. The compound alone did not affect the number of correct responses. These results suggest that STM is closely related to the cholinergic system, and that idebenone may have an improving effect on the impairment of STM induced by a decreased cholinergic activity.

Animals↗
PubMed1984

Thyrotropin-releasing hormone (TRH) and its analog (DN-1417): interaction with pentobarbital in oxygen consumption and cyclic AMP formation of rat cerebral cortex slices.

Effects of TRH or its analog DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L- prolinamide ) and pentobarbital, alone or in combination, on oxygen consumption and cyclic AMP formation in rat cerebral cortex slices were investigated. The oxygen consumption of rat cerebral cortex slices as measured with a Warburg apparatus, increased linearly over time (0 to 60-min incubation at 37C). Addition of pentobarbital (1 to 7 x 10-4M) inhibited oxygen consumption, in a concentration-dependent manner, up to 45% of control. A concomitant application of DN-1417 (10-5M) or TRH (10-4M) and pentobarbital (5 x 10-4M) led to a partial recovery of the pentobarbital effect. The similar anti-pentobarbital effects were observed with the addition of carbachol (10-4M) or dibutyryl cyclic AMP (10-3M), but not norepinephrine (10-4M) or dopamine (10-4M). DN-1417, TRH, carbachol, norepinephrine or dopamine at 10-4M stimulated cyclic AMP formation in the cerebral cortex slices. Addition of pentobarbital (1 to 7 x 10-4M) inhibited the cyclic AMP formation, in a concentration-dependent manner. DN-1417, TRH or carbachol at 10-4M but not norepinephrine or dopamine at 10-4M significantly reversed the reduction of cyclic AMP formation induced by pentobarbital (5 x 10-4M). Atropine (10-4M) almost completely abolished DN-1417-, TRH- and carbachol-induced cyclic AMP formation in the presence and absence of pentobarbital.

Animals↗
PubMed1984

A TRH analog (DN-1417): motor stimulation with rearing related to catecholaminergic mechanisms in rats.

The effect of an analog of TRH, gamma-butyrolactone-gamma-carbonyl-histidyl-prolinamide citrate (DN-1417) on motor activity was studied in rats. Peripheral administration of DN-1417 (0.2-20 mg/kg, i.p.) caused a significant, dose-dependent increase in total spontaneous motor activity, with a definite increase in rearing behaviour. Both increases in spontaneous motor activity and rearing behaviour were markedly inhibited by pretreatment with chlorpromazine (1, 5 mg/kg, i.p.), haloperidol (0.1, 0.5 mg/kg, i.p.), pimozide (1 mg/kg, i.p.) or alpha-methyltyrosine (250 mg/kg, i.p.). Only stimulation of rearing behaviour was selectively attenuated by phenoxybenzamine (5 mg/kg, i.p.) or FLA-63 (25 mg/kg, i.p.) at doses producing no significant effect on spontaneous motor activity. Although propranolol (10 mg/kg, i.p.) and methysergide (10 mg/kg, i.p.) had no effect, atropine (10 mg/kg, i.p.) and mecamylamine (10 mg/kg, i.p.) respectively potentiated and counteracted the effects of DN-1417. Concerning the stimulation of spontaneous motor activity, the nucleus accumbens and lateral hypothalamic area were most sensitive to DN-1417, and the lateral hypothalamic area was the most sensitive site for the stimulation of rearing. Furthermore, DN-1417 (5 X 10(-5) M) significantly enhanced the spontaneous release of [3H]dopamine from the rat nucleus accumbens slices in vitro. These findings indicate that the motor stimulatory action of DN-1417 appears to be mediated primarily via a dopaminergic mechanism by enhancing the release of dopamine from nerve terminals, including the nucleus accumbens in the mesolimbic dopamine system, and, in turn, the rearing may be mediated via noradrenergic mechanism.

Animals↗
PubMed1984

[Physiological and biochemical study of temporary cerebral ischemic rats produced by bilateral vertebral and carotid artery occlusion].

We investigated the changes of behavioral, electrophysiological and biochemical parameters during and after global cerebral ischemia in rats. Global cerebral ischemia was produced by the temporary occlusion of both common carotid arteries 24 hr after the permanent electrocauterization of bilateral vertebral arteries. Just before recirculation following 10 or 30 min of cerebral ischemia, loss of righting reflex, flattenning of cortical EEG activity, and detrimental decrease of ATP content and marked increase of lactate content in the cerebrum were observed. The alterations of all parameters completely recovered within 60 min after recirculation in 10-min cerebral ischemic rats. However, the 30-min cerebral ischemic rats showed almost no recovery after recirculation, suggesting that some irreversible damages are produced in the cerebrum of the 30-min ischemic rat. On the other hand, it was found that the auditory brain stem evoked response (ABER) and ATP content in the pons plus medulla were only slightly affected by the ischemic procedure, which indicates that the ischemic damages do not ensue in the lower part of the brain stem.

Animals↗
PubMed1984

[Neurochemical study of the temporary cerebral ischemic rats produced by bilateral vertebral and carotid artery occlusion].

The effects of global cerebral ischemia on neurochemical parameters in the brain were examined in rats. Global cerebral ischemia was produced by temporary occlusion of the bilateral common carotid arteries 24 hr after the permanent electrocauterization of the bilateral vertebral arteries. In 10-min cerebral ischemic rats, the brain levels of monoamine were unaltered. The brain levels of gamma-aminobutyric acid (GABA), which increased about 1.5-fold just before recirculation, almost recovered to the levels of the sham operated group (sham ope. levels) within 5 min after recirculation. The brain levels of cyclic AMP (cAMP), although they altered a little just before recirculation, increased about 6-fold 1 min after recirculation, and they recovered to the sham ope. levels 3-5 min later. In 30-min cerebral ischemic rats, the brain levels of monoamine decreased to about 40% of the sham ope. levels just before recirculation, and norepinephrine (NE) and 5-hydroxytryptamine (5-HT) levels did not recover within 30 min after recirculation in the telencephalon. The brain GABA levels which increased about 2-fold just before recirculation, recovered to the sham ope. levels in all brain regions by 30-min recirculation except for the levels in cerebral cortex and cerebellum. The brain cAMP levels which increased about 3.5-fold 10 min after recirculation, almost recovered 20 min later. However, the cAMP levels in the telencephalon decreased to levels lower than the sham ope. levels 30 min after recirculation. It is suggested that the changes of these neurochemical parameters in the telencephalon are related in part to the abnormalities of behavior and EEG activity which have been already reported.

Acetylcholinesterase↗
PubMed1984

Beneficial effect of idebenone (CV-2619) on cerebral ischemia-induced amnesia in rats.

An experimental model of amnesia induced by cerebral ischemia after one-trial passive avoidance learning was established to test the effects of a novel compound, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone, CV-2619), and some commonly used drugs in rats. One day after the vertebral artery was electrocauterized bilaterally, the common carotid artery was transiently occluded bilaterally to produce cerebral ischemia. The amnesia was estimated by the response latency for a rat to step from a light safety compartment to a dark compartment in which a foot-shock was given. The results of the retention test given 24 hr after the ischemia indicated that amnesia was successfully produced when the 200-600 sec ischemia was provided within 20 min after the avoidance learning. The effects of drugs on the amnesia induced by a 200-sec ischemia immediately after the avoidance learning were as follows: CV-2619 (10, 30 mg/kg, i.p. or p.o.) given before the retention test significantly increased the response latency, indicating a reversal effect on the amnesia. Physostigmine (0.1, 0.2 mg/kg, i.p.) and arginine-vasopressin (10 micrograms/kg, s.c.) were also effective, and calcium hopantenate (500 mg/kg, p.o.) showed a slight reversal action. Furthermore, CV-2619 (10 mg/kg, i.p.), given before or after the ischemia, significantly inhibited the appearance of amnesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Amnesia↗
PubMed1983

Thyrotropin-releasing hormone (TRH) and its analog (DN-1417): interaction with pentobarbital in choline uptake and acetylcholine synthesis of rat brain slices.

TRH or its analog DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-proliamide) given 15 min after intravenous (i.v.) administration of pentobarbital (30 mg/kg) markedly shortened the pentobarbital-induced sleeping time in rats. This effect was almost completely abolished by intracerebroventricular pretreatment with atropine methylbromide (20 micrograms/rat), thereby suggesting the involvement of cholinergic mechanism. The action mechanism was investigated using rat brain slices. TRH (10(-6)-10(-4)M) or DN-1417 (10(-7)-10(-5)M) caused significant increases in the uptake of [3H]-choline into striatal slices. TRH(10(-4)M) or DN-1417(10(-5)M) also stimulated the conversion of [3H]-choline to [3H]-acetylcholine in striatal slices. A 30% reduction of acetylcholine synthesis from [3H]-choline in hippocampal slices and a 40% reduction of [3H]-choline uptake in slices of cerebral cortex, hippocampus and hypothalamus were observed in rats pretreated with pentobarbital (60 mg/kg, i.v.). TRH or DN-1417 (20 mg/kg, i.v.) given 15 min after the administration of pentobarbital markedly reversed both of the pentobarbital effects. Direct application of pentobarbital (5 X 10(-4)M) to slices in vitro also caused a 20-40% reduction of [3H]-choline uptake of cerebral cortex, hippocampus and diencephalon. A concomitant application of TRH(10(-4)M) or DN-1417(10(-5)M) and pentobarbital abolished the pentobarbital effect. These results provide neurochemical evidence that the antagonistic effects of TRH and DN-1417 on pentobarbital-induced narcosis are closely related to alterations in the rat brain choline uptake and acetylcholine synthesis, which are considered to be measures of the activity of cholinergic neurons.

Acetylcholine↗
PubMed1983

A TRH analog (DN-1417): effects on local cerebral glucose utilization in conscious and pentobarbitalized rats determined by the autoradiographic 2-deoxy-[14C]glucose method.

Effects of a TRH (thyrotropin-releasing hormone) analog, DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate), with regard to the rate of local cerebral glucose utilization (LCGU) were assessed using the autoradiographic 2-deoxy-D-[14C]glucose method to clarify the possible sites of action in conscious and pentobarbitalized rats. DN-1417 (0.5-5 mg/kg, i.v.) significantly shortened the pentobarbital-induced sleeping time in a dose dependent manner, and this effect of DN-1417 was reduced by intracerebroventricular (i.c.v.) pretreatment with atropine methylbromide (20 micrograms). DN-1417 (5 mg/kg, i.v.) by itself slightly increased the LCGU in the thalamus dorsomedial nucleus and mammillary body and significantly increased it in the septal nucleus. Pentobarbital (30 mg/kg, i.v.) alone produced a marked and diffuse reduction in LCGU throughout the brain at a rate of about 46% of the control. DN-1417 (5 mg/kg, i.v.) markedly reversed the reduction of LCGU induced by pentobarbital. The antagonistic effect of DN-1417 in LCGU was about twice as potent as that of TRH. Locally, significant reversal effects by DN-1417 were observed in the hypothalamus, septal nucleus, hippocampus, mammillary body, thalamus dorsomedial nucleus, caudate-putamen, nucleus accumbens, pontine gray matter and so on. These actions of DN-1417 were almost completely abolished in all areas except for the visual cortex under the condition of pretreatment with atropine methylbromide (20 micrograms, i.c.v.). On the other hand, pimozide (1 mg/kg, i.p.) augmented the actions of DN-1417. Thus, DN-1417 seems to act on the level of consciousness via a reticulo-thalamo-cortical system, and reverses the LCGU reduction induced by pentobarbital via a cholinergic mechanism. The hypothalamus appears to be a crucial site in mediation of the antagonistic action of DN-1417 on pentobarbital.

Animals↗
PubMed1983

Increase in rat regional brain cyclic nucleotides by thyrotropin-releasing hormone (TRH) and its analog DN-1417.

The effects of thyrotropin-releasing hormone (TRH) and its analog gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate (DN-1417) on adenosine 3',5'-monophosphate (cyclic AMP) and guanosine 3',5'-monophosphate (cyclic GMP) levels in rat brain were investigated using a radioimmunoassay method. The time course of elevation of these nucleotides in various brain regions after administration of DN-1417 showed a peak at 5 to 15 min followed by a gradual decrease. DN-1417 (1 to 10 mg/kg i.p.) caused a dose-related increase in cyclic AMP levels in the cerebellum, cerebral cortex, striatum, nucleus accumbens, thalamus, hypothalamus and brain stem; whereas significant increases in cyclic GMP were observed in the cerebellum, nucleus accumbens and brain stem. TRH (3 to 10 mg/kg i.p.) caused significant increases of cyclic AMP in the cerebellum, cerebral cortex, nucleus accumbens, thalamus and brain stem and also caused an increase in cerebellar cyclic GMP. With one exception, DN-1417, apomorphine (Apo), methamphetamine (MAP) (all, 3 mg/kg i.p.)- and TRH (10 mg/kg i.p.)-induced increases in cyclic nucleotides were blocked by pimozide (1 mg/kg i.p., 4 hr before), a dopamine receptor blocker; the exception was a TRH-induced increase in cerebellar cyclic GMP. These increases were not blocked by propranolol (10 mg/kg i.p., 30 min before), an adrenergic beta-receptor blocker. alpha-Methyl-p-tyrosine (alpha-MT, 250 mg/kg i.p., 4 hr before), a tyrosine hydroxylase inhibitor, almost completely blocked DN-1417- and MAP-induced increases in cyclic nucleotides, slightly blocked TRH-effects, and had no effect on Apo-effects. These in vivo results were confirmed in an in vitro system using brain slices. The addition of DN-1417 (10(-4) M) or TRH (10(-3) M) significantly enhanced the spontaneous [3H]-dopamine and [3H]-norepinephrine release from the superfused slices of the rat nucleus accumbens and cerebral cortex in vitro. The addition of DN-1417 (10(-4) M) or TRH (10(-4) M) had no effect on the activities of adenylate cyclase and guanylate cyclase, although only a high concentration (10(-3) M) of DN-1417 inhibited the cyclic AMP- and cyclic GMP-hydrolytic activities in various brain region homogenates. These results suggest that DN-1417 does not produce an increase in the levels of cyclic nucleotides by direct receptor-enzyme activation, but that DN-1417 like MAP causes the increase through endogenous catecholaminergic, particularly dopaminergic activation.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1983

[Effects of pentylenetetrazol on conflict behavior and interactions with anxiolytics in rats].

Effects of pentylenetetrazol (PTZ) on conflict behavior were studied using a punished water-lick (conflict) paradigm in rats. PTZ (5-20 mg/kg, ip) produced a dose-related enhancement of conflict behavior as demonstrated by a suppression of lick responding in low shock intensity (1.3-2.0 mA). Furthermore, PTZ (2-20 mg/kg, ip) clearly antagonized the release of punished responding induced by diazepam (5 mg/kg, ip), chlordiazepoxide (10 mg/kg i.p.) or meprobamate (75 mg/kg, ip) when a high intensity of shock (2.5 or 3 mA) was used. Bemegride also showed a similar suppressive effect on the anticonflict action of diazepam. However, bicuculline, picrotoxin or strychnine neither enhanced conflict behavior nor inhibited the anticonflict action of diazepam, even in high doses. In addition, PTZ (10 or 20 mg/kg, ip) did not show any significant effect on unpunished drinking or flinch-jump threshold, suggesting that the conflict enhancing action of PTZ may not be due to the secondary action including decrease in drive for drinking or increase in sensitivity to shock. These results suggest that PTZ may exert facilitation of conflict behavior or suppression of the anticonflict action of anxiolytics via an activation of the conflict generating mechanisms.

Animals↗
PubMed1983

Modification of dopaminergic transmission by thyrotropin-releasing hormone.

TRH may act on the brain independently of its effects on the pituitary, and some of the CNS actions of TRH are probably closely related to brain catecholamines. TRH enhanced SMA by systemic injection (20 mg/kg, i.p.) or direct microinjection (10 micrograms) of TRH into the nucleus accumbens (ACB), one of the nerve terminal sites of the mesolimbic dopaminergic system, in rats. Prevention of this TRH effect by pretreatment with haloperidol or pimozide, a DA receptor blocker, or alpha-MT, an inhibitor of tyrosine hydroxylase, indicated that the SMA stimulatory action of TRH was the result of an enhancement of the release of DA from the nerve terminals. In rats lesioned unilaterally in the nigrostriatal DA pathway by 6-OHDA, high doses of TRH given i.p. (100 mg/kg) or into the nonlesioned caudate nucleus (50 micrograms) produced a circling toward the lesioned side which was suppressed by haloperidol or alpha-MT. The in vitro study demonstrated that TRH (5 X 10(-4)M) enhanced the release of preloaded [3H]DA from the slices of ACB after stable spontaneous DA release was established under superfusion, while a higher concentration (10(-2)M) was required to enhance the DA release from striatal slices. These in vitro studies supported the findings in investigation in vivo. In addition, TRH (2.5-20 mg/kg) markedly enhanced the circling behavior induced by L-DOPA or apomorphine in mice with unilateral caudate nucleus lesions induced by injection of 6-OHDA. In the 6-OHDA lesioned mice treated with TRH, DA-induced cyclic AMP formation was clearly enhanced in the striatal slices taken from the lesioned side but not from the intact side. In conclusion, TRH in low doses facilitates the DA presynaptic transmission by increasing the release of this amine from the ACB and also the DA postsynaptic transmission by increasing DA-stimulated cyclic AMP formation in striatum supersensitized with 6-OHDA. Endogenous TRH may play a physiological role as a modulator on DA transmission in CNS.

Animals↗
PubMed1983

[Interaction with cholinergic drugs in reversal of cycloheximide-induced amnesia by thyrotropin-releasing hormone and its analog DN-1417 in mice].

The reversal effect of drugs on experimental amnesia was studied using one-trial passive avoidance task in mice. Cycloheximide (120 mg/kg) given sc 30 min before the acquisition of avoidance response caused amnesia by showing short latency to enter from the safety compartment into the shocked compartment in the retention test conducted 24 hours later. In these cycloheximide-treated animals, physostigmine (0.1 mg/kg), thyrotropin-releasing hormone (TRH: 10-20 mg/kg) and DN-1417 (5-20 mg/kg) given sc 15-60 min before the retention test markedly prolonged response latency, indicating reversal of amnesia. The effects of all these drugs were almost completely antagonized by anticholinergic drug, scopolamine (0.4-10 mg/kg). Although physostigmine when administered in conjunction with TRH potentiated the reversal effect, there was no potentiation with DN-1417. Since these drugs did not affect test performance in the cycloheximide-treated mice which had experienced no foot-shock, it is unlikely that the amnesia-reversing effect of the drugs was a result of non-specific suppression on motor activity. These results suggest that cholinergic activation reverses cycloheximide-induced amnesia, and TRH and DN-1417, while they showed a difference in the action of potentiation with physostigmine, may also activate a retrieval process of memory by mediation of cholinergic mechanism.

Amnesia↗
PubMed1982

Radioimmunoassay for an analog of thyrotrophin-releasing hormone, gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide (DN-1417).

A heterologous radioimmunoassay method was established to determine plasma levels of gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide (DN-1417). As this compound is unstable in the incubation buffer, we introduced a conversion step. DN-1417 in the plasma was extracted with a solution of isopropanol-isobutylamine (4 : 1) and incubation was performed at room temperature for 2 h for the conversion of DN-1417 into N-[2-hydroxy-4-(isobutylcarbamoyl)butyryl]-L-histidyl-L-prolinamide (DN-isobutylamide). 125I-labeled 2-hydroxy-4-carboxybutyryl-L-histidyl-L-prolinamide and antisera, which was raised in the rabbit using an esterified derivative of DN-1417 conjugated with BSA as an antigen, were used for a sensitive radioimmunoassay of DN-isobutylamide. In this system, 0.2 ng DN-isobutylamide/ml plasma, equivalent to 0.16 ng DN-1417/ml, was detected and there was no apparent interference from its metabolites. The within-assay coefficients of variation were 7.6% at 7.73 ng/tube and 13.7% at 1.32 ng/tube. The between-assay coefficients of variation were 16.1% at 6.43 ng/tube and 12.2% at 1.20 ng/tube. The mean recovery rate of the assay system was 76.0 +/- 3.2% (S.E.M.).

Animals↗