title: First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models.
abstract: JAK4D, a first-in-class thyrotropin-releasing hormone (TRH)-based compound, is a prospective therapeutic candidate offering a multifaceted approach to treating neurodegeneration and other CNS conditions. The purpose of these studies was to determine the ability of JAK4D to bind to TRH receptors in human brain and to evaluate its neuropharmacological effects in neurodegenerative animal models. Additionally, JAK4D brain permeation was examined in mouse, and initial toxicology was assessed in vivo and in vitro. We report that JAK4D bound selectively with nanomolar affinity to native TRH receptors in human hippocampal tissue and showed for the first time that these receptors are pharmacologically distinct from TRH receptors in human pituitary, thus revealing a new TRH receptor subtype which represents a promising neurotherapeutic target in human brain. Systemic administration of JAK4D elicited statistically significant and clinically-relevant neuroprotective effects in three established neurodegenerative animal models: JAK4D reduced cognitive deficits when administered post-insult in a kainate (KA)-induced rat model of neurodegeneration; it protected against free radical release and neuronal damage evoked by intrastriatal microdialysis of KA in rat; and it reduced motor decline, weight loss, and lumbar spinal cord neuronal loss in G93A-SOD1 transgenic Amyotrophic Lateral Sclerosis mice. Ability to cross the blood-brain barrier and a clean initial toxicology profile were also shown. In light of these findings, JAK4D is an important tool for investigating the hitherto-unidentified central TRH receptor subtype reported herein and an attractive therapeutic candidate for neurodegenerative disorders.
authors.affiliation: Academic Unit of Neurology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. Electronic address: kellyja@tcd.ie.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Kelly
authors.affiliation: Department of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Noreen T
authors.initials: NT
authors.lastname: Boyle
authors.affiliation: MedEL Directorate, Robert Mayne Day Hospital, St. James's Hospital, Dublin 8, Ireland.
authors.forename: Natalie
authors.initials: N
authors.lastname: Cole
authors.affiliation: Academic Unit of Neurology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Gillian R
authors.initials: GR
authors.lastname: Slator
authors.affiliation: NEUROFARBA Department, University of Florence, Viale G Pieraccini 6, 50139 Firenze, Italy.
authors.forename: M Alessandra
authors.initials: MA
authors.lastname: Colivicchi
authors.affiliation: NEUROFARBA Department, University of Florence, Viale G Pieraccini 6, 50139 Firenze, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Stefanini
authors.affiliation: Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Oliviero L
authors.initials: OL
authors.lastname: Gobbo
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Gaia A
authors.initials: GA
authors.lastname: Scalabrino
authors.affiliation: UCD School of Veterinary Medicine, Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Sinead M
authors.initials: SM
authors.lastname: Ryan
authors.affiliation: Academic Unit of Neurology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Marwa
authors.initials: M
authors.lastname: Elamin
authors.affiliation: Department of Statistics, Lloyd Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Cathal
authors.initials: C
authors.lastname: Walsh
authors.affiliation: Academic Unit of Neurology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Alice
authors.initials: A
authors.lastname: Vajda
authors.affiliation: Academic Unit of Neurology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Goggin
authors.affiliation: Smurfit Insitute of Genetics, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Matthew
authors.initials: M
authors.lastname: Campbell
authors.affiliation: Neurology and Molecular and Cellular Pharmacology, Miller School of Medicine, 1951 NW 7th Ave Suite 240, Miami, FL 33136, USA.
authors.forename: Deborah C
authors.initials: DC
authors.lastname: Mash
authors.affiliation: Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Shane M
authors.initials: SM
authors.lastname: O'Mara
authors.affiliation: UCD School of Veterinary Medicine, Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: David J
authors.initials: DJ
authors.lastname: Brayden
authors.affiliation: Ross University School of Veterinary Medicine, Basseterre, St. Kitts, West Indies; UCD School of Veterinary Medicine, Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: John J
authors.initials: JJ
authors.lastname: Callanan
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Keith F
authors.initials: KF
authors.lastname: Tipton
authors.affiliation: NEUROFARBA Department, University of Florence, Viale G Pieraccini 6, 50139 Firenze, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Della Corte
authors.affiliation: OI Pharma Partners Ltd., Weston, Hertfordshire, UK.
authors.forename: Jackie
authors.initials: J
authors.lastname: Hunter
authors.affiliation: UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Kathy M
authors.initials: KM
authors.lastname: O'Boyle
authors.affiliation: Formerly of School of Biology and Biochemistry, Medical Biology Centre, Queen's University, Belfast BT9 7BL, N. Ireland, UK.
authors.forename: Carvell H
authors.initials: CH
authors.lastname: Williams
authors.affiliation: Academic Unit of Neurology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Orla
authors.initials: O
authors.lastname: Hardiman
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D018938:Caco-2 Cells; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000378:metabolism*; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D018025:Receptors, Thyrotropin-Releasing Hormone; D013973:Thyrotropin-Releasing Hormone
keywords: JAK4D; Neurodegeneration; Neuroprotection; Novel central TRH receptor-subtype; TRH receptors; Thyrotropin-releasing hormone