The Experts below are selected from a list of 156 Experts worldwide ranked by ideXlab platform
Hidetoshi Asai - One of the best experts on this subject based on the ideXlab platform.
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Metabolic Abnormalities Caused by 3-Acetylpyridine in the Cerebral Motor Regions of Rats: Partial Recovery by Thyrotropin-Releasing Hormone
Japanese Journal of Pharmacology, 2020Co-Authors: Kiyoshi Kinoshita, Hidetoshi Asai, Yumi Watanabe, Yuzo MatsuokaAbstract:Abstract Although 3-acetylpyridine (3-AP) induces several motor disturbances and it degenerates the olivocerebellar pathway, abnormalities caused by 3-AP in cerebral motor regions remain to be elucidated. Here we investigated the metabolic changes caused by 3-AP (75 mg/kg, i.p.) on local cerebral glucose utilization (LCGU) in various brain regions. The effects of anti-ataxic agents, thyrotropin-releasing hormone (TRH) (10 mg/kg, i.p.) and its mimetic agent Taltirelin hydrate (1 mg/kg, i.p.), on the 3-AP-induced change in LCGU were also investigated. The LCGU in the nuclei of the basal ganglia, thalamus, limbic structures and brainstem of 3-AP-treated rats was significantly lower than that of naive animals. However 3-AP increased the LCGU of the cerebellar nuclei. TRH restored depressed LCGU in the substantia nigra and ventral tegmental area. TRH tended to restore the lowered LCGU in several nuclei of 3-AP-treated rats. Moreover, Taltirelin further increased the LCGU in the cerebellar nuclei. These results suggest that the motor disturbance of the 3-AP-treated rats may be due to not only degeneration of the olivocerebellar pathway but also dysfunction of the several areas that play a role in motor coordination. Moreover, the anti-ataxic action by TRH could result from metabolic restoration of the multiple motor-coordination-related areas.
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reversal of hemorrhagic shock in rats using the metabolically stable thyrotropin releasing hormone analog Taltirelin hydrate
Journal of Receptors and Signal Transduction, 2011Co-Authors: Hidetoshi Asai, Yumi Watanabe, Rikako YamauchikohnoAbstract:We investigated the effect of Taltirelin hydrate ((−)-N-[(S)-hexahydro-1-methyl- 2,6-dioxo-4-pyrimidinyl-carbonyl]-L-histidyl-L-prolinamide tetrahydrate; Taltirelin), a metabolically stable thyrotropin-releasing hormone (TRH) analog, on circulatory function, respiratory function, and viable time after bleeding in urethane-anesthetized rats. Massive volume-controlled bleeding caused marked reductions in mean arterial pressure (MAP) and respiratory rate (RR). The vital signs of control rats were lost within an average of 23 min after bleeding. Intravenous administration of Taltirelin (0.03−0.3 mg/kg) and TRH (1 and 3 mg/kg) immediately after bleeding accelerated recovery of MAP and RR, and prolonged viable time in a dose-dependent manner. The potency of Taltirelin in accelerating MAP and RR recovery and prolonging viable time was higher when compared with that of TRH. In addition, recovery of MAP and RR and the extension of viable time by Taltirelin were inhibited by preintraperitoneal administration of atropine sulfate, which is a centrally acting muscarinic antagonist, but not by that of atropine methylbromide, which is a peripherally acting muscarinic antagonist. Taltirelin also recovered decreased arterial pH, bicarbonate ions, and base excess, and prevented a decrease in arterial oxygen saturation. In conclusion, the anti-shock effect of Taltirelin was more potent than that of TRH. Taltirelin activity was mediated by the central muscarinic cholinergic system. In addition, Taltirelin also corrected metabolic acidosis. These results suggest that Taltirelin could be useful in the treatment of hypovolemic shock.
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Reversal of hemorrhagic shock in rats using the metabolically stable thyrotropin-releasing hormone analog Taltirelin hydrate
Journal of Receptors and Signal Transduction, 2011Co-Authors: Hidetoshi Asai, Yumi Watanabe, Rikako Yamauchi-kohnoAbstract:We investigated the effect of Taltirelin hydrate ((−)-N-[(S)-hexahydro-1-methyl- 2,6-dioxo-4-pyrimidinyl-carbonyl]-L-histidyl-L-prolinamide tetrahydrate; Taltirelin), a metabolically stable thyrotropin-releasing hormone (TRH) analog, on circulatory function, respiratory function, and viable time after bleeding in urethane-anesthetized rats. Massive volume-controlled bleeding caused marked reductions in mean arterial pressure (MAP) and respiratory rate (RR). The vital signs of control rats were lost within an average of 23 min after bleeding. Intravenous administration of Taltirelin (0.03–0.3 mg/kg) and TRH (1 and 3 mg/kg) immediately after bleeding accelerated recovery of MAP and RR, and prolonged viable time in a dose-dependent manner. The potency of Taltirelin in accelerating MAP and RR recovery and prolonging viable time was higher when compared with that of TRH. In addition, recovery of MAP and RR and the extension of viable time by Taltirelin were inhibited by preintraperitoneal administration of atr...
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lack of behavioral tolerance by repeated treatment with Taltirelin hydrate a thyrotropin releasing hormone analog in rats
Pharmacology Biochemistry and Behavior, 2005Co-Authors: Hidetoshi Asai, Rikako Yamauchikohno, Toshio Asahi, Michio Yamamura, Akira SaitoAbstract:Abstract In order to determine whether acute tolerance develops by Taltirelin hydrate ((−)- N -[( S )-hexahydro-1-methyl-2,6-dioxo-4-pyrimidinylcarbonyl]- l -histidyl- l -prolinamide tetrahydrate; Taltirelin), a thyrotropin-releasing hormone (TRH) analog, we examined the motor behavior, TRH receptors and dopamine D 2 receptors following 2 weeks treatment in rats. Taltirelin selectively bound to TRH receptors and increased the spontaneous motor activity by a single administration, suggesting that the motor effect of Taltirelin is mediated by TRH receptors. Following repeated treatment with TRH, there was a significant reduction in the increment of spontaneous motor activity. In contrast, after repeated treatment with Taltirelin at a dose that increased the motor activity to a similar extent to TRH by a single administration, there was no apparent change in its motor effect. In accord with the motor activity, we found a significant reduction in the [ 3 H]methyl-TRH binding to TRH receptors in the brain following repeated treatment with TRH but not Taltirelin. However, the [ 3 H]spiperone binding to dopamine D 2 receptors in the corpus striatum did not change by repeated Taltirelin and TRH treatments. Thus, the down-regulation of TRH receptors would be a main cause of the behavioral tolerance. These results suggest that Taltirelin hardly develops the behavioral tolerance due to the lack of down-regulation of TRH receptors.
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Diversity of Thyrotropin-Releasing Hormone Receptors in the Pituitary and Discrete Brain Regions of Rats
Japanese Journal of Pharmacology, 1999Co-Authors: Hidetoshi Asai, Michio Yamamura, Kiyoshi Kinoshita, Yuzo MatsuokaAbstract:Abstract In order to analyze the receptor properties of central nervous system (CNS)-stimulant thyrotropin-releasing hormone ( L -pyroglutamyl- L -histidyl- L -prolinamide, TRH), we evaluated the binding of TRH and its analog Taltirelin hydrate ((—)-N-[(S)-hexahydro-1-methyl-2,6-dioxo-4-pyrimidinylcar-bonyl]- L -histidyl- L -prolinamide tetrahydrate; Taltirelin, TA-0910) in rat anterior pituitary and several brain regions. There was a specific binding of [3H]methyl TRH (MeTRH) in the anterior pituitary, hypothalamus, brain stem, cerebral cortex and cerebellum with Kd values of 1.0–1.6 nM. The inhibition of [3H]MeTRH binding by TRH and Taltirelin was monophasic in the anterior pituitary, hypothalamus and brain stem with Ki values of 6.3 – 8.0 nM and 145.5 – 170.4 nM for TRH and Taltirelin, respectively. In contrast, the biphasic inhibition was revealed in the cerebral cortex and cerebellum. The IQ values for TRH and Taltirelin were 4.1 – 4.3 nM and 67.8 – 73.4 nM for the high affinity binding site and 3.6–4.2 μM and 82.3–197.5 μM for the low affinity binding site, respectively. Addition of 100 μM GTP or its analog 5'-guanylylimidodiphos-phate (Gpp[NH]p) affected neither the biphasic inhibition by TRH nor that by Taltirelin. Thus the results suggest the presence of distinct high and low affinity TRH receptors in the CNS in contrast to the pituitary.
Rikako Yamauchikohno - One of the best experts on this subject based on the ideXlab platform.
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reversal of hemorrhagic shock in rats using the metabolically stable thyrotropin releasing hormone analog Taltirelin hydrate
Journal of Receptors and Signal Transduction, 2011Co-Authors: Hidetoshi Asai, Yumi Watanabe, Rikako YamauchikohnoAbstract:We investigated the effect of Taltirelin hydrate ((−)-N-[(S)-hexahydro-1-methyl- 2,6-dioxo-4-pyrimidinyl-carbonyl]-L-histidyl-L-prolinamide tetrahydrate; Taltirelin), a metabolically stable thyrotropin-releasing hormone (TRH) analog, on circulatory function, respiratory function, and viable time after bleeding in urethane-anesthetized rats. Massive volume-controlled bleeding caused marked reductions in mean arterial pressure (MAP) and respiratory rate (RR). The vital signs of control rats were lost within an average of 23 min after bleeding. Intravenous administration of Taltirelin (0.03−0.3 mg/kg) and TRH (1 and 3 mg/kg) immediately after bleeding accelerated recovery of MAP and RR, and prolonged viable time in a dose-dependent manner. The potency of Taltirelin in accelerating MAP and RR recovery and prolonging viable time was higher when compared with that of TRH. In addition, recovery of MAP and RR and the extension of viable time by Taltirelin were inhibited by preintraperitoneal administration of atropine sulfate, which is a centrally acting muscarinic antagonist, but not by that of atropine methylbromide, which is a peripherally acting muscarinic antagonist. Taltirelin also recovered decreased arterial pH, bicarbonate ions, and base excess, and prevented a decrease in arterial oxygen saturation. In conclusion, the anti-shock effect of Taltirelin was more potent than that of TRH. Taltirelin activity was mediated by the central muscarinic cholinergic system. In addition, Taltirelin also corrected metabolic acidosis. These results suggest that Taltirelin could be useful in the treatment of hypovolemic shock.
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lack of behavioral tolerance by repeated treatment with Taltirelin hydrate a thyrotropin releasing hormone analog in rats
Pharmacology Biochemistry and Behavior, 2005Co-Authors: Hidetoshi Asai, Rikako Yamauchikohno, Toshio Asahi, Michio Yamamura, Akira SaitoAbstract:Abstract In order to determine whether acute tolerance develops by Taltirelin hydrate ((−)- N -[( S )-hexahydro-1-methyl-2,6-dioxo-4-pyrimidinylcarbonyl]- l -histidyl- l -prolinamide tetrahydrate; Taltirelin), a thyrotropin-releasing hormone (TRH) analog, we examined the motor behavior, TRH receptors and dopamine D 2 receptors following 2 weeks treatment in rats. Taltirelin selectively bound to TRH receptors and increased the spontaneous motor activity by a single administration, suggesting that the motor effect of Taltirelin is mediated by TRH receptors. Following repeated treatment with TRH, there was a significant reduction in the increment of spontaneous motor activity. In contrast, after repeated treatment with Taltirelin at a dose that increased the motor activity to a similar extent to TRH by a single administration, there was no apparent change in its motor effect. In accord with the motor activity, we found a significant reduction in the [ 3 H]methyl-TRH binding to TRH receptors in the brain following repeated treatment with TRH but not Taltirelin. However, the [ 3 H]spiperone binding to dopamine D 2 receptors in the corpus striatum did not change by repeated Taltirelin and TRH treatments. Thus, the down-regulation of TRH receptors would be a main cause of the behavioral tolerance. These results suggest that Taltirelin hardly develops the behavioral tolerance due to the lack of down-regulation of TRH receptors.
Hitoshi Ishibashi - One of the best experts on this subject based on the ideXlab platform.
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Effect of rovatirelin, a novel thyrotropin-releasing hormone analog, on the central noradrenergic system
European Journal of Pharmacology, 2015Co-Authors: Tomoyuki Ijiro, Junichi Nabekura, Kayo Nakamura, Masanori Ogata, Hiroyuki Inada, Sumiyoshi Kiguchi, Kazuyasu Maruyama, Mamoru Kobayashi, Hitoshi IshibashiAbstract:Abstract Rovatirelin ([1-[-[(4S,5S)-(5-methyl-2-oxo oxazolidin-4-yl) carbonyl]-3-(thiazol-4-yl)- l -alanyl]-(2R)-2-methylpyrrolidine) is a novel synthetic agent that mimics the actions of thyrotropin-releasing hormone (TRH). The aim of this study was to investigate the electrophysiological and pharmacological effects of rovatirelin on the central noradrenergic system and to compare the results with those of another TRH mimetic agent, Taltirelin, which is approved for the treatment of spinocerebellar degeneration (SCD) in Japan. Rovatirelin binds to the human TRH receptor with higher affinity (Ki=702 nM) than Taltirelin (Ki=3877 nM). Rovatirelin increased the spontaneous firing of action potentials in the acutely isolated noradrenergic neurons of rat locus coeruleus (LC). The facilitatory action of rovatirelin on the firing rate in the LC neurons was inhibited by the TRH receptor antagonist, chlordiazepoxide. Reduction of the extracellular pH increased the spontaneous firing of LC neurons and rovatirelin failed to increase the firing frequency further, indicating an involvement of acid-sensitive K+ channels in the rovatirelin action. In in vivo studies, oral administration of rovatirelin increased both c-Fos expression in the LC and extracellular levels of noradrenaline (NA) in the medial prefrontal cortex (mPFC) of rats. Furthermore, rovatirelin increased locomotor activity. The increase in NA level and locomotor activity by rovatirelin was more potent and longer acting than those by Taltirelin. These results indicate that rovatirelin exerts a central nervous system (CNS)-mediated action through the central noradrenergic system, which is more potent than Taltirelin. Thus, rovatirelin may have an orally effective therapeutic potential in patients with SCD.
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Taltirelin a thyrotropin releasing hormone analog alleviates mechanical allodynia through activation of descending monoaminergic neurons in persistent inflammatory pain
Brain Research, 2011Co-Authors: Junichi Nabekura, Hitoshi IshibashiAbstract:Abstract Thyrotropin-releasing hormone (TRH) and its analogs have been reported to modulate descending monoaminergic inhibitory neurons, resulting in antinociception. However, it remains unknown whether TRH exerts an antiallodynic effect during persistent pain. Here, we investigated the action of Taltirelin, a stable TRH analog, on mechanical allodynia in mice with inflammatory persistent pain induced by an injection of complete Freund's adjuvant into the hindpaw. Systemic administration of 1.0 mg/kg Taltirelin markedly reduced mechanical allodynia. This effect was abolished by the 6-hydroxydopamine (6-OHDA)-induced depletion of central noradrenaline. While intraperitoneal injection of the α 1 -adrenoceptor antagonist prazosin had no effect, intraperitoneal and intrathecal administration of the α 2 -adrenoceptor antagonist yohimbine prevented the antiallodynic action of Taltirelin. In addition, dl -p-chlorophenylalanine (PCPA)-induced depletion of serotonin (5-HT) and intraperitoneal and intrathecal injection of the 5-HT 1A receptor antagonist WAY-100635 blocked the effect of Taltirelin on allodynia. These findings suggest that Taltirelin alleviates mechanical allodynia in inflammatory persistent pain by modulating the descending noradrenergic and serotonergic neuronal pathways via indirect activation of spinal α 2 -adrenergic and 5-HT 1A receptors.
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Excitation of locus coeruleus noradrenergic neurons by thyrotropin‐releasing hormone
The Journal of Physiology, 2009Co-Authors: Hitoshi Ishibashi, Yoshihisa Nakahata, Junichi NabekuraAbstract:Locus coeruleus (LC) noradrenergic neurons are implicated in a variety of functions including the regulation of vigilance and the modulation of sensory processing. Thyrotropin-releasing hormone (TRH) is an endogenous neuropeptide that induces a variety of behavioural changes including arousal and antinociception. In the present study, we explored whether the activity of LC noradrenergic neurons is modulated by TRH. Using current-clamp recording from isolated rat LC neurons, we found that TRH increased the firing rate of spontaneous action potentials. The TRH action was mimicked by TRH analogues including Taltirelin and TRH-gly. In voltage-clamp recording at a holding potential of −50 mV, TRH produced an inward current associated with a decrease in the membrane K+ conductance. This current was inhibited by the TRH receptor antagonist chlordiazepoxide. Following inhibition of the pH-sensitive K+ conductance by extracellular acidification, the TRH response was fully inhibited. The TRH-induced current was also inhibited by the phospholipase C (PLC) inhibitor U-73122, but not by the protein kinase C inhibitor chelerythrine nor by chelation of intracellular Ca2+ by BAPTA. The recovery from the facilitatory action of TRH on the spike frequency was markedly inhibited by a high concentration of wortmannin. These results suggest that TRH activates LC noradrenergic neurons by decreasing an acid-sensitive K+ conductance via PLC-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate. The present findings demonstrate that TRH activates LC neurons and characterize the underlying signalling mechanisms. The action of TRH on LC neurons may influence a variety of CNS functions related to the noradrenergic system which include arousal and analgesia.
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Excitation of locus coeruleus noradrenergic neurons by thyrotropin-releasing hormone.
The Journal of physiology, 2009Co-Authors: Hitoshi Ishibashi, Yoshihisa Nakahata, Junichi NabekuraAbstract:Locus coeruleus (LC) noradrenergic neurons are implicated in a variety of functions including the regulation of vigilance and the modulation of sensory processing. Thyrotropin-releasing hormone (TRH) is an endogenous neuropeptide that induces a variety of behavioural changes including arousal and antinociception. In the present study, we explored whether the activity of LC noradrenergic neurons is modulated by TRH. Using current-clamp recording from isolated rat LC neurons, we found that TRH increased the firing rate of spontaneous action potentials. The TRH action was mimicked by TRH analogues including Taltirelin and TRH-gly. In voltage-clamp recording at a holding potential of 50 mV, TRH produced an inward current associated with a decrease in the membrane K+ conductance. This current was inhibited by the TRH receptor antagonist chlordiazepoxide. Following inhibition of the pH-sensitive K+ conductance by extracellular acidification, the TRH response was fully inhibited. The TRH-induced current was also inhibited by the phospholipase C (PLC) inhibitor U-73122, but not by the protein kinase C inhibitor chelerythrine nor by chelation of intracellular Ca2+ by BAPTA. The recovery from the facilitatory action of TRH on the spike frequency was markedly inhibited by a high concentration of wortmannin. These results suggest that TRH activates LC noradrenergic neurons by decreasing an acid-sensitive K+ conductance via PLC-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate. The present findings demonstrate that TRH activates LC neurons and characterize the underlying signalling mechanisms. The action of TRH on LC neurons may influence a variety of CNS functions related to the noradrenergic system which include arousal and analgesia.
Marvin C. Gershengorn - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of the effects of chemotherapy-induced fatigue and pharmacological interventions in multiple mouse behavioral assays
Behavioural Brain Research, 2018Co-Authors: John P. Dougherty, Danielle A. Springer, Mary J. Cullen, Marvin C. GershengornAbstract:Abstract Fatigue is a common symptom in many diseases and disorders and can reduce quality of life, yet lacks an adequate pharmacological intervention. To identify and develop such interventions, and to better understand fatigue, additional preclinical research is necessary. However, despite numerous mouse behavioral assays reportedly detecting fatigue-like behavior, the assumption that fatigue-like behavior is detected in many assays has not been validated through a cross-assay study. Thus, we modeled fatigue in mice by administering 5-fluorouracil, a chemotherapy drug known to cause fatigue in humans and fatigue-like behavior in mice, then evaluated its effects via voluntary wheel running activity (VWRA), locomotor activity in the open field test (OFT), immobility in the forced swim test (FST), and distance run in the treadmill fatigue test (TFT) and treadmill exercise capacity test. Additionally, Taltirelin or methylphenidate was administered to alleviate fatigue-like behavior. As a result of 5-fluorouracil treatment, VWRA and the TFT were markedly reduced, indicating fatigue. The OFT, FST, and treadmill exercise capacity test, however, failed to detect fatigue-like behavior. Interestingly, both Taltirelin and methylphenidate alleviated fatigue-like behavior in TFT. These data suggest that, of the current assays, only the TFT and VWRA should be expected to detect fatigue-like behavior. Moreover, this study provides additional evidence that Taltirelin may provide a novel treatment for chemotherapy-induced fatigue and warrants further evaluation as an anti-fatigue therapeutic.
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Taltirelin alleviates fatigue like behavior in mouse models of cancer related fatigue
Pharmacological Research, 2017Co-Authors: John P. Dougherty, Mary J. Cullen, Brian S Wolff, Leorey N Saligan, Marvin C. GershengornAbstract:Fatigue affects most cancer patients and has numerous potential causes, including cancer itself and cancer treatment. Cancer-related fatigue (CRF) is not relieved by rest, can decrease quality of life, and has no FDA-approved therapy. Thyrotropin-releasing hormone (TRH) has been proposed as a potential novel treatment for CRF, but its efficacy against CRF remains largely untested. Thus, we tested the TRH analog, Taltirelin (TAL), in mouse models of CRF. To model fatigue, we used a mouse model of chemotherapy, a mouse model of radiation therapy, and mice bearing colon 26 carcinoma tumors. We used the treadmill fatigue test to assess fatigue-like behavior after treatment with TAL. Additionally, we used wild-type and TRH receptor knockout mice to determine which TRH receptor was necessary for the actions of TAL. Tumor-bearing mice displayed muscle wasting and all models caused fatigue-like behavior, with mice running a shorter distance in the treadmill fatigue test than controls. TAL reversed fatigue-like behavior in all three models and the mouse TRH1 receptor was necessary for the effects of TAL. These data suggest that TAL may be useful in alleviating fatigue in all cancer patients and provide further support for evaluating TAL as a potential therapy for CRF in humans.
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Thyrotropin-Releasing Hormone Receptor Type 1 (TRH-R1), not TRH-R2, Primarily Mediates Taltirelin Actions in the CNS of Mice
Neuropsychopharmacology, 2013Co-Authors: Nanthakumar Thirunarayanan, Bruce M Raaka, Marvin C. GershengornAbstract:Thyrotropin-releasing hormone receptor type 2 (TRH-R2), not TRH-R1, has been proposed to mediate the CNS effects of TRH and its more effective analog Taltirelin (TAL). Consistent with this idea, TAL exhibited higher binding affinity and signaling potency at mouse TRH-R2 than TRH-R1 in a model cell system. We used TRH-R1 knockout (R1ko), R2ko and R1/R2ko mice to determine which receptor mediates the CNS effects of TAL. There was no TRH-R1 mRNA in R1ko and R1/R2ko mice and no TRH-R2 mRNA in R2ko and R1/R2ko mice. Specific [^3H]MeTRH binding to whole brain membranes was 5% of wild type (WT) for R1ko mice, 100% for R2ko mice and 0% for R1/R2ko mice, indicating TRH-R1 is the predominant receptor expressed in the brain. In arousal assays, TAL shortened sleep time with pentobarbital sedation in WT and R2ko mice by 44 and 49% and with ketamine/xylazine sedation by 66 and 55%, but had no effect in R1ko and R1/R2ko mice. In a tail flick assay of nociception, TAL increased response latency by 65 and 70% in WT and R2ko mice, but had no effect in R1ko and R1/R2ko mice. In a tail suspension test of depression-like behavior, TAL increased mobility time by 49 and 37% in WT and R2ko mice, but had no effect in R1ko and R1/R2ko mice. Thus, in contrast to the generally accepted view that the CNS effects of TAL are mediated by TRH-R2, these effects are mediated primarily if not exclusively by TRH-R1 in mice.
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Taltirelin is a superagonist at the human thyrotropin releasing hormone receptor
Frontiers in Endocrinology, 2012Co-Authors: Nanthakumar Thirunarayanan, Bruce M Raaka, Marvin C. GershengornAbstract:Taltirelin (TAL) is a thyrotropin-releasing hormone (TRH) analog that is approved for use in humans in Japan. In this study, we characterized TAL binding to and signaling by the human TRH receptor (TRH-R) in a model cell system. We found that TAL exhibited lower binding affinities than TRH and lower signaling potency via the inositol-1,4,5-trisphosphate/calcium pathway than TRH. However, TAL exhibited higher intrinsic efficacy than TRH in stimulating inositol-1,4,5-trisphosphate second messenger generation. This is the first study that elucidates the pharmacology of TAL at TRH-R and shows that TAL is a superagonist at TRH-R. We suggest the superagonism exhibited by TAL may in part explain its higher activity in mediating CNS effects in humans compared to TRH.
Stella M Papa - One of the best experts on this subject based on the ideXlab platform.
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trh analog Taltirelin protects dopaminergic neurons from neurotoxicity of mptp and rotenone
Frontiers in Cellular Neuroscience, 2018Co-Authors: Cong Zheng, Guiqin Chen, Weiqi Zeng, Qiwei Peng, Ji Wang, Chi Cheng, Xiaoman Yang, Yan Xu, Zhentao Zhang, Stella M PapaAbstract:Dopaminergic neurons loss is one of the main pathological characters of Parkinson’s disease (PD), while no suitable neuroprotective agents have been in clinical use. Thyrotropin-releasing hormone (TRH) and its analogs protect neurons from ischemia and various cytotoxins, but whether the effect also applies in PD models remain unclear. Here, we showed that Taltirelin, a long-acting TRH analog, exhibited the neuroprotective effect in both cellular and animal models of PD. The in vitro study demonstrated that Taltirelin (5 μM) reduced the generation of reactive oxygen species (ROS) induced by MPP+ or rotenone, alleviated apoptosis and rescued the viability of SH-SY5Y cells and rat primary midbrain neurons. Interestingly, SH-SY5Y cells treated with Taltirelin also displayed lower level of p-tau (S396) and asparagine endopeptidase (AEP) cleavage products, tau N368 and α-synuclein N103 fragments, accompanied by a lower intracellular monoamine oxidase-B (MAO-B) activity. In the subacute MPTP-induced and chronic rotenone-induced PD mice models, we found Taltirelin (1 mg/kg) significantly improved the locomotor function and preserved dopaminergic neurons in the substantia nigra (SN). In accordance with the in vitro study, Taltirelin down-regulated the levels of p-tau (S396), p-α-synuclein (S129) tau N368 and α-synuclein N103 fragments in SN and striatum. Together, this study demonstrates that Taltirelin may exert neuroprotective effect via inhibiting MAO-B and reducing the oxidative stress and apoptosis, preventing AEP activation and its subsequent pathological cleavage of tau and α-synuclein, thus provides evidence for Taltirelin in protective treatment of PD.
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trh analog Taltirelin improves motor function of hemi pd rats without inducing dyskinesia via sustained dopamine stimulating effect
Frontiers in Cellular Neuroscience, 2018Co-Authors: Cong Zheng, Guiqin Chen, Weiqi Zeng, Qiwei Peng, Ji Wang, Chi Cheng, Xiaoman Yang, Yan Xu, Zhentao Zhang, Stella M PapaAbstract:Thyrotropin-releasing hormone (TRH) and its analogs are able to stimulate the release of the endogenic dopamine (DA) in the central nervous system. However, this effect has not been tested in the Parkinson’s disease (PD), which is characterized by the DA deficiency due to the dopaminergic neurons loss in the substantia nigra. Here, we investigated the therapeutic effect of Taltirelin, a long-acting TRH analog on 6-hydroxydopamine-lesioned hemi-Parkinsonian rat model. 1–10 mg/kg Taltirelin i.p. administration significantly improved the locomotor function and halted the electrophysiological abnormities of PD animals without inducing dyskinesia even with high-dose for 7 days treatment. Microdialysis showed that Taltirelin gently and persistently promoted DA release in the cortex and striatum, while L-DOPA induced a sharp rise of DA especially in the cortex. The DA-releasing effect of Taltirelin was alleviated by reserpine, vanoxerine (GBR12909) or AMPT, indicating a mechanism involving vesicular monoamine transporter-2 (VMAT-2), dopamine transporter (DAT) and tyrosine hydroxylase (TH). The in vivo and in vitro experiments further supported that Taltirelin affected the regulation of TH expression in striatal neurons, which was mediated by p-ERK1/2. Together, this study demonstrated that Taltirelin improved motor function of hemi-PD rats without inducing dyskinesia, thus supporting a further exploration of Taltirelin for PD treatment.