The role of Thyrotropin Releasing Hormone in aging and neurodegenerative diseases

Daimon, Caitlin M.; Chirdon, Patrick; Maudsley, Stuart; Martin, Bronwen

doi:10.7726/ajad.2013.1003

Cited by 38 publications

(40 citation statements)

References 195 publications

(213 reference statements)

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“…Tyrotropin‐releasing hormone (TRH) concentration, a neuropeptide primarily known for its role as central regulator of the hypothalamic–pituitary–thyroid axis, was shown to be decreased in the hippocampus of AD patients compared to elderly controls. In in vitro neuronal cell cultures, depletion of TRH was shown to enhance tau phosphorylation via changes in the activity of several kinases (Luo et al, ; Luo and Stopa, ; Daimon et al, ). Moreover, there is evidence to suggest that THs are required during early development for high rates of microtubule assembly (Fellous et al, ).…”

Section: Discussionmentioning

confidence: 99%

PTU‐induced hypothyroidism in rats leads to several early neuropathological signs of Alzheimer's disease in the hippocampus and spatial memory impairments

et al. 2014

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The multifactorial causes impacting the risk of developing sporadic forms of Alzheimer's disease (AD) remain to date poorly understood. Epidemiologic studies in humans and research in rodents have suggested that hypothyroidism could participate in the etiology of AD. Recently, we reported that adult-onset hypothyroidism in rats favors β-amyloid peptide production in the hippocampus. Here, using the same hypothyroidism model with the antithyroid molecule propythiouracyl (PTU), we further explored AD-related features, dysfunctional cell-signaling mechanisms and hippocampal-dependent learning and memory. In vivo MRI revealed a progressive decrease in cerebral volume of PTU-treated rats. In the hippocampus, hypothyroidism resulted in tau hyperphosphorylation and increases in several proinflammatory cytokines. These modifications were associated with impaired spatial memory and reduced hippocampal expression of signaling molecules important for synaptic plasticity and memory, including neurogranin, CaMKII, ERK, GSK3β, CREB, and expression of the transcription factor EGR1/Zif268. These data strengthen the idea that hypothyroidism represents an important factor influencing the risk of developing sporadic forms of AD.

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Section: Discussionmentioning

confidence: 99%

PTU‐induced hypothyroidism in rats leads to several early neuropathological signs of Alzheimer's disease in the hippocampus and spatial memory impairments

et al. 2014

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“…The hippocampal TRH receptor subtype could be a variant of TRHR1 or a different, previously-unknown binding site for TRH. (Daimon et al, 2013) surmised that, similar to gonadotropin-releasing hormone receptor, TRHR1 in humans may exist in more than one conformation and that different agonists may bind selectively to one or other conformer leading to activation of different downstream signals. Alternatively, differences in signal activation may be attributable to differences in the quaternary structure of receptors, e.g., polymeric assemblies (George et al, 2002).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

“…Potential clinical application of activation of this central system in treating a wide range of CNS disorders has long been recognized (Gary et al, 2003;Griffiths, 1987;Kelly, 1995) and was recently reviewed (Daimon et al, 2013). TRH's remarkable neuroprotective actions include attenuation of multiple constituents of secondary pathways that lead to neuronal cell death (Faden et al, 2005;Jantas et al, 2009) and improvement of cellular bioenergetics, ionic homeostasis, and M A N U S C R I P T…”

Section: Introductionmentioning

confidence: 99%

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

Kelly¹,

Boyle²,

Cole³

et al. 2015

Neuropharmacology

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Hardiman, O., 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, Neuropharmacology (2014), doi: 10.1016/j.neuropharm.2014.09.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPTABSTRACT 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.

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“…The hypothalamic TRH system interplays with the hypothalamicepituitaryeadrenal axis, thereby regulating stress and stressinduced neuropathology (Helmreich et al, 2005;Bahls and Carvalho, 2004;Daimon et al, 2013). Patients with depression show a blunted TSH response to TRH injection (Duval et al, 2010;Hage and Azar, 2012).…”

Section: Introductionmentioning

confidence: 98%

TRH and TRH receptor system in the basolateral amygdala mediate stress-induced depression-like behaviors

Choi

Kim

et al. 2015

Neuropharmacology

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The role of Thyrotropin Releasing Hormone in aging and neurodegenerative diseases

Cited by 38 publications

References 195 publications

PTU‐induced hypothyroidism in rats leads to several early neuropathological signs of Alzheimer's disease in the hippocampus and spatial memory impairments

PTU‐induced hypothyroidism in rats leads to several early neuropathological signs of Alzheimer's disease in the hippocampus and spatial memory impairments

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

TRH and TRH receptor system in the basolateral amygdala mediate stress-induced depression-like behaviors

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