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.
journal_name
Neuropharmacologyjournal_title
Neuropharmacologyauthors
Kelly JA,Boyle NT,Cole N,Slator GR,Colivicchi MA,Stefanini C,Gobbo OL,Scalabrino GA,Ryan SM,Elamin M,Walsh C,Vajda A,Goggin MM,Campbell M,Mash DC,O'Mara SM,Brayden DJ,Callanan JJ,Tipton KF,Della Corte L,Hunter J,doi
10.1016/j.neuropharm.2014.09.024subject
Has Abstractpub_date
2015-02-01 00:00:00pages
193-203eissn
0028-3908issn
1873-7064pii
S0028-3908(14)00331-1journal_volume
89pub_type
杂志文章abstract::A genetic component is associated with the development of many forms of epilepsy. Recently, mutations in the GABAA receptor have been linked to several inherited epilepsies. One of these mutations is a non-conservative change of alanine to aspartate in the third transmembrane domain of the alpha1 subunit. To determine...
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journal_title:Neuropharmacology
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journal_title:Neuropharmacology
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journal_title:Neuropharmacology
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journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2004.07.021
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journal_title:Neuropharmacology
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journal_title:Neuropharmacology
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journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2014.11.020
更新日期:2015-04-01 00:00:00