title: Effect of rovatirelin, a novel thyrotropin-releasing hormone analog, on the central noradrenergic system.
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=702nM) than taltirelin (Ki=3877nM). 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.
authors.affiliation: Pharmacology Research Laboratory R&D, Kissei Pharmaceutical Co., Ltd., 4365-1, Kashiwabara, Hotaka, Azumino Nagano 399-8304, Japan. Electronic address: tomoyuki_ijiro@pharm.kissei.co.jp.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ijiro
authors.affiliation: Division of Homeostatic Development, Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Physiology, Kitasato University School of Allied Health Sciences, Sagamihara 252-0373, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Ogata
authors.affiliation: Department of Physiology, Kitasato University School of Allied Health Sciences, Sagamihara 252-0373, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inada
authors.affiliation: Pharmacology Research Laboratory R&D, Kissei Pharmaceutical Co., Ltd., 4365-1, Kashiwabara, Hotaka, Azumino Nagano 399-8304, Japan.
authors.forename: Sumiyoshi
authors.initials: S
authors.lastname: Kiguchi
authors.affiliation: Pharmacology Research Laboratory R&D, Kissei Pharmaceutical Co., Ltd., 4365-1, Kashiwabara, Hotaka, Azumino Nagano 399-8304, Japan.
authors.forename: Kazuyasu
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: Division of Homeostatic Development, Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Nabekura
authors.affiliation: Pharmacology Research Laboratory R&D, Kissei Pharmaceutical Co., Ltd., 4365-1, Kashiwabara, Hotaka, Azumino Nagano 399-8304, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of Physiology, Kitasato University School of Allied Health Sciences, Sagamihara 252-0373, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ishibashi
mesh_terms: D000200:Action Potentials; D000284:Administration, Oral; D059331:Adrenergic Neurons / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D023303:Oxazolidinones / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011759:Pyrrolidines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000819:agonists / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D008024:Ligands; D023303:Oxazolidinones; D016760:Proto-Oncogene Proteins c-fos; D011759:Pyrrolidines; D018025:Receptors, Thyrotropin-Releasing Hormone; C065049:TA 0910; D013973:Thyrotropin-Releasing Hormone; C000607550:rovatirelin; D009638:Norepinephrine
keywords: Chlordiazepoxide (PubChem CID 2712); Locomotor activity; Locus coeruleus; Noradrenaline; Rovatirelin; Rovatirelin (PubChem CID: 9951059); TRH (PubChem CID 32281); TRH analog; Taltirelin (PubChem CID 114750); Thyrotropin-releasing hormone (TRH)