The Experts below are selected from a list of 90 Experts worldwide ranked by ideXlab platform

Kiyoshi Kimura - One of the best experts on this subject based on the ideXlab platform.

  • Protein Kinases Are Involved in Prolonged Acetylcholine Release from Rat Hippocampus Induced by Thyrotropin‐Releasing Hormone Analogue NS‐3
    Journal of neurochemistry, 2002
    Co-Authors: Michiko Oka, Yoshinori Itoh, Yojiro Ukai, Yoshiaki Yoshikuni, Kiyoshi Kimura
    Abstract:

    The effects of various protein kinase inhibitors on acetylcholine release from the rat hippocampus induced by the local application of NS-3 (Montirelin hydrate, CG-3703), a thyrotropin-releasing hormone analogue, into the medial septum-diagonal band were examined using in vivo microdialysis. Perfusion of NS-3 (1 microM) into the medial septum-diagonal band for 20 min produced a pronounced and prolonged increase in the hippocampal acetylcholine efflux. Pretreatment of the medial septum-diagonal band with either K-252a, a nonselective protein kinase inhibitor, or selective protein kinase A inhibitor H-89 almost completely blocked the acetylcholine efflux evoked by NS-3, and selective protein kinase C inhibitor calphostin C inhibited the action of NS-3. On the other hand, NS-3 (0.1-10 microM) or TRH (1-100 microM) increased the cyclic AMP efflux from the medial septum-diagonal band in a concentration-dependent manner, as measured by microdialysis. These findings suggest that protein kinases A and C in the neurons of the medial septum-diagonal band are involved in the mechanism of the prolonged stimulation of acetylcholine release from the hippocampus induced by thyrotropin-releasing hormone and its analogue, NS-3.

  • Montirelin hydrate (NS-3), a TRH analog, improved the disturbance of consciousness caused by head concussion and pentobarbital in mice
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 1996
    Co-Authors: Takeshi Mushiroi, Rika Shibahara, Masaru Tamura, Takako Shimizu, Yoshinori Itoh, Yojiro Ukai, Yoshiaki Yoshikuni, Kiyoshi Kimura
    Abstract:

    Effects of a novel TRH analog, Montirelin hydrate (NS-3), on the coma caused by head concussion and narcosis induced by pentobarbital were compared with those of TRH in mice. Head concussion caused a behavioral comatose state with loss of the righting reflex and spontaneous motor activity. NS-3 shortened the latent periods to the recovery of the righting reflex (0.03-0.1 mg/kg, i.v.) and spontaneous motor activity (0.1 mg/kg, i.v.) following the head concussion. In the case of TRH, higher doses were needed to induce such effects. NS-3 (0.1-0.3 mg/kg, i.v.) reversed the pentobarbital-induced narcosis in a dose-dependent manner. A similar effect was elicited by 30- to 100-fold higher doses of TRH than NS-3. The analeptic effect of NS-3 in the pentobarbital-narcotized mice was antagonized by SCH23390, a dopamine D1 antagonist or by the combined treatment with prazosin and scopolamine, while neither prazosin nor scopolamine alone antagonized the analeptic effect of NS-3. Taken together with the finding that NS-3 did not bind to dopamine, adrenaline or muscarine receptors, it is suggested that NS-3 may restore the disturbance of consciousness by activating the brain dopamine, noradrenaline and acetylcholine neurons without stimulating these receptors directly.

  • Enhancement of brain noradrenaline and dopamine turnover by thyrotropin-releasing hormone and its analogue NS-3 in mice and rats
    Pharmacology & toxicology, 1996
    Co-Authors: Yoshinori Itoh, Yojiro Ukai, Yoshiaki Yoshikuni, Akira Yamazaki, Kiyoshi Kimura
    Abstract:

    The effects of intravenous injections of thyrotropin-releasing hormone and its analog NS-3 (Montirelin hydrate, CG3703) on the dynamics of brain monoamines were examined in mice and rats. In mice, both NS-3 (0.1-1 mg/kg) and thyrotropin-releasing hormone (10 and 30 mg/kg) increased the concentrations of 4-hydroxy-3-methoxyphenylglycol, 3,4-dihydroxyphenylacetic acid and homovanillic acid. The turnover rates, estimated either by depletion of catecholamines after treatment with alpha-methyl-p-tyrosine or by probenecid-induced accumulation of homovanillic acid, were enhanced by these peptides. In contrast, none of the compounds had any influence on the serotonin turnover. In rats, both NS-3 and thyrotropin-releasing hormone produced a regionally specific increase in the concentrations of the catecholamine metabolites. A microdialysis study demonstrated that NS-3 significantly increased the release of dopamine in the nucleus accumbens as well as the striatum of conscious rats, while thyrotropin-releasing hormone caused a weak but significant enhancement of dopamine release only in the nucleus accumbens. These findings indicate that NS-3 was far more potent than thyrotropin-releasing hormone in facilitating the turnover of catecholamines without affecting serotonin turnover in the mouse and rat brain.

  • Montirelin hydrate (NS-3), a TRH analog, improved disturbance of consciousness in cats: electroencephalographical studies
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 1996
    Co-Authors: Yojiro Ukai, Yoshiaki Yoshikuni, Ogasawara Takashi, Kiyoshi Kimura
    Abstract:

    Central effects of Montirelin hydrate (NS-3) were electroencephalographically investigated in cats with experimentally induced disturbance of consciousness. All experiments were conducted under the gallamine-immobilized and artificially ventilated acute experimental condition. NS-3 and TRH produced EEG activation in cats with lesions in the midbrain reticular formation in a dose-dependent manner. Similar effects were observed in cats with bilateral lesions of the posterior hypothalamic area. These effects of NS-3 were 30 to 100 times more potent than those of TRH. NS-3 at doses higher than 0.003 mg/kg restored the suppressed EEG dose-dependently in cats with cerebral ischemia produced by clamping the bilateral common carotid arteries and basilar artery. TRH showed no effect at a dose of 10 mg/kg. These results indicate that NS-3 might be an effective drug for treating the disturbance of consciousness.

  • NS-3, a TRH-analog, reverses memory disruption by stimulating cholinergic and noradrenergic systems.
    Pharmacology biochemistry and behavior, 1996
    Co-Authors: Takashi Ogasawara, Masaru Tamura, Yoshinori Itoh, Yojiro Ukai, Yoshiaki Yoshikuni, Kiyoshi Kimura
    Abstract:

    The effects of a TRH-analog, N[[(3R,6R)-6-methyl-5-oxo-3-thiomorpholinyl]carbonyl]-L-histidyl-L - prolinamide tetrahydrate (NS-3, CG3703, Montirelin hydrate) were compared with those of physostigmine on learning and memory disruption in the passive avoidance response (PAR) induced by either electrolytic lesion of the nucleus basalis magnocellularis (NBM) or by treatment with the noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) in rats. a) In NBM-lesioned rats, both NS-3 and physostigmine significantly reversed disruption of memory consolidation examined 15 min after the training session when these drugs were injected IP immediately after the training session. In addition, reversal by NS-3 (0.1 mg/kg) of the disruption of memory was observed even in the retention test conducted 24 h after the training session. b) NS-3 (0.5 mg/kg) significantly reversed the disruption of memory retrieval, when the drug was administered 15 min before the test session. c) DSP4 (50 mg/kg IP) caused memory disruption when the retention tests were conducted between 1 and 48 h after the acquisition session. NS-3 (0.1 mg/kg), but not physostigmine, significantly reversed the disruption of memory induced by DSP4 treatment. These findings suggest that the consistent antiamnestic action of NS-3 is due to the enhancement of both central cholinergic and noradrenergic systems, possibly via facilitation of the release of these transmitters.

Nobuyoshi Sumi - One of the best experts on this subject based on the ideXlab platform.

  • VASCULAR IRRITABILITY STUDY OF Montirelin HYDRATE (NS-3) INJECTION IN RABBITS
    The Journal of Toxicological Sciences, 1995
    Co-Authors: Ryoji Shibata, Tatsuya Ishii, Yasuyuki Nishiguchi, Keiko Iwakura, Nobuyoshi Sumi
    Abstract:

    A vascular irritability study of Montirelin hydrate (NS-3) injection, a new drug for the treatment of disturbance of consciousness, was conducted in Japanese white rabbits. The concentration of Montirelin hydrate was 4 mg/ml. Saline and 0.75% acetic acid were used as negative and positive control, respectively. In a part of the ear vein, 0.05 ml of each compound was allowed to remain for 3 min after intravenous injections once a day for 8 days. Inflammation in peri-venous region and thrombus were macroscopically observed in injection sites of rabbits with the Montirelin hydrate injection group. However, no changes were seen with the negative control group. Histopathological examination revealed periphlebitis, desquamation of endothelial cells and thrombus in rabbits given Montirelin hydrate injection or saline. But incidence and degree of periphlebitis caused by Montirelin hydrate injection were higher than those caused by saline. On the other hand, the irritating changes caused by 0.75% acetic acid were severer than those by Montirelin hydrate injection. These results show that Montirelin hydrate injection has a very weak vascular irritability in the ear of rabbits.

  • Single dose toxicity studies of metabolite, degradation product and impurity of Montirelin hydrate (NS-3) in mice
    The Journal of Toxicological Sciences, 1995
    Co-Authors: Yasuyuki Nishiguchi, Keiko Iwakura, Motokuni Nakazawa, Takaaki Oka, Yoshimi Hagidai, Nobuyoshi Sumi
    Abstract:

    Montirelin hydrate (NS-3) is a new drug for the treatment of disturbance of consciousness. The single dose toxicity studies of its degradation product and impurity (CNK-603) and its metabolite (CNK-6004) were conducted in Slc: ddY mice. The Compounds Were administered intravenously to male and female mice. Deaths occurred in both sexes of mice receiving more than 125 mg/kg of CNK-603. There were no treatment-related effects on survival in both sexes of mice receiving doses up to 2, 000 mg/kg of CNK-6004. Approximate lethal dose of CNK-603 was 125 mg/kg and lethal dose of CNK-6004 was more than 2, 000 mg/kg. Decrease in locomotor activity was observed in mice receiving the two compounds. Tremor, prone position and dyspnea were seen in mice receiving CNK-603. The body weight showed no changes attributable to the dosing of the two compounds in mice. In autopsies, congestion and hemorrhage in the lung were observed in dead mice given CNK-603. There were no remarkable changes in mice given CNK-6004. These results show that the lethal dose of CNK-603 is over 4 times lower than that of Montirelin hydrate, and that CNK-6004 is less toxic than Montirelin hydrate.

  • Mutagenicity studies of Montirelin hydrate (NS-3)
    The Journal of Toxicological Sciences, 1995
    Co-Authors: Keiko Iwakura, E. Kitayama, Y Hamasu, H. Tamura, Y. Yamashita, Hisamitsu Nagasawa, Masataka Watanabe, Nobuyoshi Sumi
    Abstract:

    Montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was examined for mutagenicity in the reverse mutation test, the chromosome aberration test in vitro, and the micronucleus test in mice. The reverse mutation test was performed at dose range of 156.25-5, 000 μg/plate using Salmonella typhimurium strains, TA1535, TA100, TA1537, and TA98, and Escherichia coli WP2uvrA. The drug did not increase reverent colonies significantly in any of the test strains with or without metabolic activation system (S-9mix). The chromosome aberration test was carried out at dose range of 300-4, 800 μg/ml using cultured Chinese hamster lung cells (CHL/IU). No significant increases of the frequencies of cells with chromosomal aberrations were observed with or without metabolic activations. The micronucleus test was conducted in the bone marrow cells of Slc : ddY male mice. Mice were given the drug by a single intraperitoneal administration at doses of 0, 250, 500, 1, 000, and 2, 000 mg/kg. There were no significant increases in the frequencies of micronucleated polychromatic erythrocytes at any dose levels. These results show that Montirelin hydrate has no mutagenic activity in vitro or in vivo.

  • TWENTY-SIX-WEEK INTRAVENOUS TOXICITY STUDY OF Montirelin HYDRATE (NS-3) IN RATS FOLLOWED BY 9-WEEK RECOVERY TEST
    The Journal of Toxicological Sciences, 1995
    Co-Authors: Shigenori Furukawa, Keiko Iwakura, Ikuo Nishida, Mikito Kikumori, Yuzou Taniguchi, Tsukao Nishimori, Seitaro Ishibashi, Nobuyoshi Sumi
    Abstract:

    A repeated dose toxicity study of Montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in beagle dogs. Male and female dogs were given the drug intravenously for 26 weeks at doses of 0 (control), 0.02, 0.2, 2 and 20 mg/kg. After discontinuation of the treatment, a 9-week recovery test was also conducted. No deaths related to the treatment were observed. Nasal discharge in all dose groups, and tremor, salivation and emesis in the 0.2 mg/kg group and over were seen. Decrease in body weight gain was observed in the 2 and 20 mg/kg groups. There were no abnormalities in body temperature, and food and water consumptions. Urinalysis and electrocardiographic, ophthalmoscopic and hematologic examinations failed to show any abnormalities attributable to the treatment. In blood chemical examination, increase in T3 level was observed in the 2 and 20 mg/kg groups of females. There were no pathological findings attributable to the treatment. The changes mentioned above were satisfactorily reversible. The nasal discharge seen in the 0.02 mg/kg group was considered to be of no toxicological significance. These results show that the NOAEL of Montirelin hydrate is 0.02 mg/kg for 26-week repeated dose toxicity in dogs.

  • Reproductive and developmental toxicity studies of Montirelin hydrate (1)--Fertility study in rats by intravenous administration
    The Journal of Toxicological Sciences, 1995
    Co-Authors: T Morinaga, S Fujii, K Yasuhira, Masataka Watanabe, Shigenori Furukawa, Mikito Kikumori, Nobuyoshi Sumi
    Abstract:

    A study of fertility and early embryonic development to implantation of Montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in Sprague-Dawley rats. Male rats were given the drug intravenously from 63 days before mating to the end of mating period and female rats from 14 days before mating to day 7 of pregnancy ; the dose levels for both males and females were 0 (control), 0.02, 1 and 50 mg/kg. The females were sacrificed on day 20 of pregnancy for examination of their fetuses. In the 50 mg/kg group, tremor, disappeared within some minutes, was observed during administration period in all animals. Food and water consumptions increased in the females and body weight gain was suppressed in the males. Moreover prolonged estrus cycle was observed at early period of the administration in the females, but it recovered at late period of the administration. However, there were no toxicities in the males and females in the 1 mg/kg or less groups. The drug had no adverse effects on reproductive function of the parent animals, or on development of fetuses. These results show that the NOAEL of Montirelin hydrate are 1 mg/kg for general toxicity in parent animals, and 50 mg/kg for reproductive function of the parent animals and for development of fetuses.

Yojiro Ukai - One of the best experts on this subject based on the ideXlab platform.

  • Protein Kinases Are Involved in Prolonged Acetylcholine Release from Rat Hippocampus Induced by Thyrotropin‐Releasing Hormone Analogue NS‐3
    Journal of neurochemistry, 2002
    Co-Authors: Michiko Oka, Yoshinori Itoh, Yojiro Ukai, Yoshiaki Yoshikuni, Kiyoshi Kimura
    Abstract:

    The effects of various protein kinase inhibitors on acetylcholine release from the rat hippocampus induced by the local application of NS-3 (Montirelin hydrate, CG-3703), a thyrotropin-releasing hormone analogue, into the medial septum-diagonal band were examined using in vivo microdialysis. Perfusion of NS-3 (1 microM) into the medial septum-diagonal band for 20 min produced a pronounced and prolonged increase in the hippocampal acetylcholine efflux. Pretreatment of the medial septum-diagonal band with either K-252a, a nonselective protein kinase inhibitor, or selective protein kinase A inhibitor H-89 almost completely blocked the acetylcholine efflux evoked by NS-3, and selective protein kinase C inhibitor calphostin C inhibited the action of NS-3. On the other hand, NS-3 (0.1-10 microM) or TRH (1-100 microM) increased the cyclic AMP efflux from the medial septum-diagonal band in a concentration-dependent manner, as measured by microdialysis. These findings suggest that protein kinases A and C in the neurons of the medial septum-diagonal band are involved in the mechanism of the prolonged stimulation of acetylcholine release from the hippocampus induced by thyrotropin-releasing hormone and its analogue, NS-3.

  • Montirelin hydrate (NS-3), a TRH analog, improved the disturbance of consciousness caused by head concussion and pentobarbital in mice
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 1996
    Co-Authors: Takeshi Mushiroi, Rika Shibahara, Masaru Tamura, Takako Shimizu, Yoshinori Itoh, Yojiro Ukai, Yoshiaki Yoshikuni, Kiyoshi Kimura
    Abstract:

    Effects of a novel TRH analog, Montirelin hydrate (NS-3), on the coma caused by head concussion and narcosis induced by pentobarbital were compared with those of TRH in mice. Head concussion caused a behavioral comatose state with loss of the righting reflex and spontaneous motor activity. NS-3 shortened the latent periods to the recovery of the righting reflex (0.03-0.1 mg/kg, i.v.) and spontaneous motor activity (0.1 mg/kg, i.v.) following the head concussion. In the case of TRH, higher doses were needed to induce such effects. NS-3 (0.1-0.3 mg/kg, i.v.) reversed the pentobarbital-induced narcosis in a dose-dependent manner. A similar effect was elicited by 30- to 100-fold higher doses of TRH than NS-3. The analeptic effect of NS-3 in the pentobarbital-narcotized mice was antagonized by SCH23390, a dopamine D1 antagonist or by the combined treatment with prazosin and scopolamine, while neither prazosin nor scopolamine alone antagonized the analeptic effect of NS-3. Taken together with the finding that NS-3 did not bind to dopamine, adrenaline or muscarine receptors, it is suggested that NS-3 may restore the disturbance of consciousness by activating the brain dopamine, noradrenaline and acetylcholine neurons without stimulating these receptors directly.

  • Enhancement of brain noradrenaline and dopamine turnover by thyrotropin-releasing hormone and its analogue NS-3 in mice and rats
    Pharmacology & toxicology, 1996
    Co-Authors: Yoshinori Itoh, Yojiro Ukai, Yoshiaki Yoshikuni, Akira Yamazaki, Kiyoshi Kimura
    Abstract:

    The effects of intravenous injections of thyrotropin-releasing hormone and its analog NS-3 (Montirelin hydrate, CG3703) on the dynamics of brain monoamines were examined in mice and rats. In mice, both NS-3 (0.1-1 mg/kg) and thyrotropin-releasing hormone (10 and 30 mg/kg) increased the concentrations of 4-hydroxy-3-methoxyphenylglycol, 3,4-dihydroxyphenylacetic acid and homovanillic acid. The turnover rates, estimated either by depletion of catecholamines after treatment with alpha-methyl-p-tyrosine or by probenecid-induced accumulation of homovanillic acid, were enhanced by these peptides. In contrast, none of the compounds had any influence on the serotonin turnover. In rats, both NS-3 and thyrotropin-releasing hormone produced a regionally specific increase in the concentrations of the catecholamine metabolites. A microdialysis study demonstrated that NS-3 significantly increased the release of dopamine in the nucleus accumbens as well as the striatum of conscious rats, while thyrotropin-releasing hormone caused a weak but significant enhancement of dopamine release only in the nucleus accumbens. These findings indicate that NS-3 was far more potent than thyrotropin-releasing hormone in facilitating the turnover of catecholamines without affecting serotonin turnover in the mouse and rat brain.

  • Montirelin hydrate (NS-3), a TRH analog, improved disturbance of consciousness in cats: electroencephalographical studies
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 1996
    Co-Authors: Yojiro Ukai, Yoshiaki Yoshikuni, Ogasawara Takashi, Kiyoshi Kimura
    Abstract:

    Central effects of Montirelin hydrate (NS-3) were electroencephalographically investigated in cats with experimentally induced disturbance of consciousness. All experiments were conducted under the gallamine-immobilized and artificially ventilated acute experimental condition. NS-3 and TRH produced EEG activation in cats with lesions in the midbrain reticular formation in a dose-dependent manner. Similar effects were observed in cats with bilateral lesions of the posterior hypothalamic area. These effects of NS-3 were 30 to 100 times more potent than those of TRH. NS-3 at doses higher than 0.003 mg/kg restored the suppressed EEG dose-dependently in cats with cerebral ischemia produced by clamping the bilateral common carotid arteries and basilar artery. TRH showed no effect at a dose of 10 mg/kg. These results indicate that NS-3 might be an effective drug for treating the disturbance of consciousness.

  • NS-3, a TRH-analog, reverses memory disruption by stimulating cholinergic and noradrenergic systems.
    Pharmacology biochemistry and behavior, 1996
    Co-Authors: Takashi Ogasawara, Masaru Tamura, Yoshinori Itoh, Yojiro Ukai, Yoshiaki Yoshikuni, Kiyoshi Kimura
    Abstract:

    The effects of a TRH-analog, N[[(3R,6R)-6-methyl-5-oxo-3-thiomorpholinyl]carbonyl]-L-histidyl-L - prolinamide tetrahydrate (NS-3, CG3703, Montirelin hydrate) were compared with those of physostigmine on learning and memory disruption in the passive avoidance response (PAR) induced by either electrolytic lesion of the nucleus basalis magnocellularis (NBM) or by treatment with the noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) in rats. a) In NBM-lesioned rats, both NS-3 and physostigmine significantly reversed disruption of memory consolidation examined 15 min after the training session when these drugs were injected IP immediately after the training session. In addition, reversal by NS-3 (0.1 mg/kg) of the disruption of memory was observed even in the retention test conducted 24 h after the training session. b) NS-3 (0.5 mg/kg) significantly reversed the disruption of memory retrieval, when the drug was administered 15 min before the test session. c) DSP4 (50 mg/kg IP) caused memory disruption when the retention tests were conducted between 1 and 48 h after the acquisition session. NS-3 (0.1 mg/kg), but not physostigmine, significantly reversed the disruption of memory induced by DSP4 treatment. These findings suggest that the consistent antiamnestic action of NS-3 is due to the enhancement of both central cholinergic and noradrenergic systems, possibly via facilitation of the release of these transmitters.

Yoshinori Itoh - One of the best experts on this subject based on the ideXlab platform.

  • Protein Kinases Are Involved in Prolonged Acetylcholine Release from Rat Hippocampus Induced by Thyrotropin‐Releasing Hormone Analogue NS‐3
    Journal of neurochemistry, 2002
    Co-Authors: Michiko Oka, Yoshinori Itoh, Yojiro Ukai, Yoshiaki Yoshikuni, Kiyoshi Kimura
    Abstract:

    The effects of various protein kinase inhibitors on acetylcholine release from the rat hippocampus induced by the local application of NS-3 (Montirelin hydrate, CG-3703), a thyrotropin-releasing hormone analogue, into the medial septum-diagonal band were examined using in vivo microdialysis. Perfusion of NS-3 (1 microM) into the medial septum-diagonal band for 20 min produced a pronounced and prolonged increase in the hippocampal acetylcholine efflux. Pretreatment of the medial septum-diagonal band with either K-252a, a nonselective protein kinase inhibitor, or selective protein kinase A inhibitor H-89 almost completely blocked the acetylcholine efflux evoked by NS-3, and selective protein kinase C inhibitor calphostin C inhibited the action of NS-3. On the other hand, NS-3 (0.1-10 microM) or TRH (1-100 microM) increased the cyclic AMP efflux from the medial septum-diagonal band in a concentration-dependent manner, as measured by microdialysis. These findings suggest that protein kinases A and C in the neurons of the medial septum-diagonal band are involved in the mechanism of the prolonged stimulation of acetylcholine release from the hippocampus induced by thyrotropin-releasing hormone and its analogue, NS-3.

  • Montirelin hydrate (NS-3), a TRH analog, improved the disturbance of consciousness caused by head concussion and pentobarbital in mice
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 1996
    Co-Authors: Takeshi Mushiroi, Rika Shibahara, Masaru Tamura, Takako Shimizu, Yoshinori Itoh, Yojiro Ukai, Yoshiaki Yoshikuni, Kiyoshi Kimura
    Abstract:

    Effects of a novel TRH analog, Montirelin hydrate (NS-3), on the coma caused by head concussion and narcosis induced by pentobarbital were compared with those of TRH in mice. Head concussion caused a behavioral comatose state with loss of the righting reflex and spontaneous motor activity. NS-3 shortened the latent periods to the recovery of the righting reflex (0.03-0.1 mg/kg, i.v.) and spontaneous motor activity (0.1 mg/kg, i.v.) following the head concussion. In the case of TRH, higher doses were needed to induce such effects. NS-3 (0.1-0.3 mg/kg, i.v.) reversed the pentobarbital-induced narcosis in a dose-dependent manner. A similar effect was elicited by 30- to 100-fold higher doses of TRH than NS-3. The analeptic effect of NS-3 in the pentobarbital-narcotized mice was antagonized by SCH23390, a dopamine D1 antagonist or by the combined treatment with prazosin and scopolamine, while neither prazosin nor scopolamine alone antagonized the analeptic effect of NS-3. Taken together with the finding that NS-3 did not bind to dopamine, adrenaline or muscarine receptors, it is suggested that NS-3 may restore the disturbance of consciousness by activating the brain dopamine, noradrenaline and acetylcholine neurons without stimulating these receptors directly.

  • Enhancement of brain noradrenaline and dopamine turnover by thyrotropin-releasing hormone and its analogue NS-3 in mice and rats
    Pharmacology & toxicology, 1996
    Co-Authors: Yoshinori Itoh, Yojiro Ukai, Yoshiaki Yoshikuni, Akira Yamazaki, Kiyoshi Kimura
    Abstract:

    The effects of intravenous injections of thyrotropin-releasing hormone and its analog NS-3 (Montirelin hydrate, CG3703) on the dynamics of brain monoamines were examined in mice and rats. In mice, both NS-3 (0.1-1 mg/kg) and thyrotropin-releasing hormone (10 and 30 mg/kg) increased the concentrations of 4-hydroxy-3-methoxyphenylglycol, 3,4-dihydroxyphenylacetic acid and homovanillic acid. The turnover rates, estimated either by depletion of catecholamines after treatment with alpha-methyl-p-tyrosine or by probenecid-induced accumulation of homovanillic acid, were enhanced by these peptides. In contrast, none of the compounds had any influence on the serotonin turnover. In rats, both NS-3 and thyrotropin-releasing hormone produced a regionally specific increase in the concentrations of the catecholamine metabolites. A microdialysis study demonstrated that NS-3 significantly increased the release of dopamine in the nucleus accumbens as well as the striatum of conscious rats, while thyrotropin-releasing hormone caused a weak but significant enhancement of dopamine release only in the nucleus accumbens. These findings indicate that NS-3 was far more potent than thyrotropin-releasing hormone in facilitating the turnover of catecholamines without affecting serotonin turnover in the mouse and rat brain.

  • NS-3, a TRH-analog, reverses memory disruption by stimulating cholinergic and noradrenergic systems.
    Pharmacology biochemistry and behavior, 1996
    Co-Authors: Takashi Ogasawara, Masaru Tamura, Yoshinori Itoh, Yojiro Ukai, Yoshiaki Yoshikuni, Kiyoshi Kimura
    Abstract:

    The effects of a TRH-analog, N[[(3R,6R)-6-methyl-5-oxo-3-thiomorpholinyl]carbonyl]-L-histidyl-L - prolinamide tetrahydrate (NS-3, CG3703, Montirelin hydrate) were compared with those of physostigmine on learning and memory disruption in the passive avoidance response (PAR) induced by either electrolytic lesion of the nucleus basalis magnocellularis (NBM) or by treatment with the noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) in rats. a) In NBM-lesioned rats, both NS-3 and physostigmine significantly reversed disruption of memory consolidation examined 15 min after the training session when these drugs were injected IP immediately after the training session. In addition, reversal by NS-3 (0.1 mg/kg) of the disruption of memory was observed even in the retention test conducted 24 h after the training session. b) NS-3 (0.5 mg/kg) significantly reversed the disruption of memory retrieval, when the drug was administered 15 min before the test session. c) DSP4 (50 mg/kg IP) caused memory disruption when the retention tests were conducted between 1 and 48 h after the acquisition session. NS-3 (0.1 mg/kg), but not physostigmine, significantly reversed the disruption of memory induced by DSP4 treatment. These findings suggest that the consistent antiamnestic action of NS-3 is due to the enhancement of both central cholinergic and noradrenergic systems, possibly via facilitation of the release of these transmitters.

  • Permeability of NS-3, a thyrotropin-releasing hormone analogue, into the brain after its systemic administration in rats : a microdialysis study
    The Journal of pharmacy and pharmacology, 1995
    Co-Authors: Yoshinori Itoh, Yojiro Ukai, Taketoshi Sugimoto, Akira Morino, Kiyoshi Kimura
    Abstract:

    The concentration of NS-3 (Montirelin hydrate, CG 3703), a thyrotropin-releasing hormone (TRH) analogue, in the cerebral cortex of urethane-anaesthetized rats was measured after its systemic administration (1 mgkg−1, i.v.), using in-vivo microdialysis coupled with a radioimmunoassay. The concentration in microdialysates was highest (24nM) during the first 20 min after injection, and it fell below the detection limit (3.5 nM) 100 min after treatment. The maximal interstitial concentration was estimated to be 0.51 μM. From these results, it is suggested that NS-3 can readily penetrate into the brain.

N Sumi - One of the best experts on this subject based on the ideXlab platform.

  • Reproductive and developmental toxicity studies of Montirelin hydrate (3)--Teratogenicity study in rabbits by intravenous administration
    The Journal of toxicological sciences, 1995
    Co-Authors: T Morinaga, S Furukawa, S Fujii, K Yasuhira, M Watanabe, N Sumi
    Abstract:

    A study of the effect of Montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, during the period of organogenesis was conducted in New Zealand white rabbits. Female rabbits were given the drug intravenously at dose levels of 0 (control), 0.01, 0.1 and 1 mg/kg from day 6 to day 18 of pregnancy. Female rabbits were sacrificed on day 29 of pregnancy for examination of their fetuses. In the 0.1 mg/kg group, food consumption decreased slightly. In the 1 mg/kg group, tachypnea, salivation and rhinorrhea were observed, and body weight and food consumption decreased and water consumption increased. The drug had no effect on the number of corpora lutea and implantations, or on fetal mortality, on fetal body weights, on placental weight, on sex ratio, or on external, visceral and skeletal development of the fetuses. These results show that the NOAEL of Montirelin hydrate are 0.1 mg/kg for general toxicity in mother animals, and 1 mg/kg for pregnancy of mother animals and for development of fetuses.

  • Five-week intravenous toxicity study of Montirelin hydrate (NS-3) in rats followed by 4-week recovery test
    The Journal of toxicological sciences, 1995
    Co-Authors: Mikito Kikumori, Katsuomi Iwakura, Ikuo Nishida, Yuzou Taniguchi, Seitaro Ishibashi, M Kojima, K Yasuhira, N Sumi
    Abstract:

    A repeated dose toxicity study of Montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in Sprague-Dawley rats. Male and female rats were given the drug intravenously for 5 weeks at doses of 0 (control), 0.05, 0.5, 5 and 50 mg/kg. After discontinuation of the treatment, a 4-week recovery test was also conducted in the 0, 0.5 and 50 mg/kg groups. No deaths related to the treatment were observed. Tremor was seen in the 50 mg/kg group. Polyuria was observed in the 5 and 50 mg/kg groups. There were decreases in body weight gain in the 0.5 mg/kg group and over of males, and in food consumption in all male dose groups and increase in water consumption in the 5 and 50 mg/kg groups. In blood chemical examination, decrease in triglyceride was observed in the 5 and 50 mg/kg groups of males. Urinalysis showed increase in urine volume in the 0.5 mg/kg group and over. Ophthalmoscopic and hematologic examinations failed to show any abnormalities attributable to the treatment. Pathological examination disclosed serous cell hypertrophy of the submandibular gland in all dose groups and increase in its organ weight in the 0.5 mg/kg group and over. The changes mentioned above were satisfactorily reversible except for the serous cell hypertrophy of the submandibular gland in the 50 mg/kg group. The decrease in food consumption and serous cell hypertrophy of the submandibular gland in the 0.05 mg/kg group were considered to be of no toxicological significance. These results show that the NOAEL of Montirelin hydrate is 0.05 mg/kg for 5-week repeated dose toxicity in rats.

  • Single dose toxicity studies of Montirelin hydrate(NS-3) in mice, rats and dogs
    The Journal of toxicological sciences, 1995
    Co-Authors: M Kikumori, K Yasuhira, I Nishida, T Nishimura, N Nakai, Y Nishiguchi, K Iwakura, H Nagasawa, N Sumi
    Abstract:

    The single dose toxicity studies of Montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, were conducted in Slc:ddY mice, Slc:SD rats, and beagle dogs of both sexes. The drug was administered intravenously (i.v.) to mice, rats and dogs, and intramuscularly (i.m.) to mice and rats. The animals were observed for 14 days after administration. LD50 values were more than 500 mg/kg and 200 mg/kg in mice and rats, respectively, by the i.v. route, and more than 20 mg/kg in both animal species by the i.m. route. In dogs, the minimum lethal dose was more than 200 mg/kg by the i.v. route. Mice that received more than 125 mg/kg by the i.v. route showed tremor and a decrease in locomotor activity during administration and for 30 min thereafter. Mice that received more than 5 mg/kg by the i.m. route showed tremor 5 min after administration and for 2 hr thereafter. Rats that received more than 50 mg/kg by the i.v. route showed tremor, and those that received 200 mg/kg by the same route showed a decrease in locomotor activity and ataxic gait, during and immediately after administration. Rats that received more than 5 mg/kg by the i.m. route showed tremor, and those that received 20 mg/kg by the same route showed salivation 5 min after administration and for 30 min thereafter. Dogs that received more than 12.5 mg/kg by the i.v. route revealed excitement, biting, vocalization, mydriasis, salivation, urination, defecation, licking chops, vomiting, increase in heart rate, panting, hyperthermia, tremor and conjunctival injection during administration and for 6 hr thereafter. The body weight, food consumption and water consumption, and pathological findings showed no changes attributable to the dosing of Montirelin hydrate in any animal.