Clinical applications of thyrotrophin-releasing hormone

Griffiths, E.C.

doi:10.1042/cs0730449

Cited by 81 publications

(33 citation statements)

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“…Because TRH is reported to have both CNS stimulant and antidepressant effects (Prange et al, 1972;Griffiths and Bennett, 1987), TRH may have an alternative therapeutic indication in narcolepsy. In the current study, we therefore assessed the effects of TRH and newer stabilized TRH analogs on daytime sleepiness and cataplexy in the canine model of narcolepsy.…”

Section: Discussionmentioning

confidence: 99%

“…TRH also has a variety of neuromodulatory effects not related to this pituitary impact. TRH stimulates cholinergic and monoaminergic turnover, depolarizes spinal motoneurons, enhances CNS arousal, modulates locomotor activity, regulates respiration, and modulates pain perception and epileptic threshold (for review, see Jackson, 1982;Metcalf, 1982;Sharif, 1985;Griffiths and Bennett, 1987;Winokur et al, 1989). Furthermore, TRH has been shown to have beneficial effects in depression (Prange et al, 1972), brain and spinal injuries (Faden, 1986), spinocerebellar degeneration (Sobue et al, 1983), and motoneuron diseases (Engel et al, 1983).…”

Section: Abstract: Thyrotropin-releasing Hormone; Narcolepsy; Cataplmentioning

confidence: 99%

“…Thyrotropin-releasing hormone (TRH), a tripeptidic hormone ( p-Glu-His-Pro-NH 2 ) originally extracted from the hypothalamus, is now known to be distributed ubiquitously in the mammalian CNS (for review, see Jackson, 1982;Metcalf, 1982;Sharif, 1985;Griffiths and Bennett, 1987;Winokur et al, 1989) and to have multiple biological effects. TRH stimulates phosphatidyl inositol turnover at the pituitary level to activate synthesis and release of thyroid-stimulating hormone (TSH) and prolactin (for review, see Kolesnick and Gershengorn, 1985).…”

Section: Abstract: Thyrotropin-releasing Hormone; Narcolepsy; Cataplmentioning

confidence: 99%

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Effects of Thyrotropin-Releasing Hormone and Its Analogs on Daytime Sleepiness and Cataplexy in Canine Narcolepsy

et al. 1997

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The therapeutic potential of thyrotropin-releasing hormone (TRH) and TRH analogs in narcolepsy, a sleep disorder characterized by abnormal rapid eye movement (REM) sleep and daytime sleepiness, was examined using the canine model. The effects of TRH and the biologically stable TRH analogs CG3703, CG3509, and TA0910 on daytime sleep and cataplexy, a symptom of abnormal REM sleep, were assessed using polysomnographic recordings and the food elicited cataplexy test (FECT), respectively. CG3703 (100 and 400 g/kg, i.v.) and TA0910 (100 and 400 g/kg, i.v.) significantly increased wakefulness and decreased sleep in narcoleptic canines, whereas TRH (400 and 1600 g/kg, i.v.) had no significant effect. TRH (25-1600 g/kg, i.v.) and all three TRH analogs, CG3703 (6.25-400 g/kg, i.v., and 0.25-16 mg/kg, p.o.), CG3509 (25-1600 g/kg, i.v.), and TA0910 (25-1600 g/kg, i.v.), significantly reduced cataplexy in canine narcolepsy. These compounds did not produce any significant side effects during behavioral assays, nor did they alter free T 3 and T 4 levels in serum even when used at doses that completely suppressed cataplexy. Although more work is needed to establish the mode of action of TRH analogs on alertness and REM sleep-related symptoms, our results suggest a possible therapeutic application for TRH analogs in human sleep disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Abstract: Thyrotropin-releasing Hormone; Narcolepsy; Cataplmentioning

confidence: 99%

Section: Abstract: Thyrotropin-releasing Hormone; Narcolepsy; Cataplmentioning

confidence: 99%

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Effects of Thyrotropin-Releasing Hormone and Its Analogs on Daytime Sleepiness and Cataplexy in Canine Narcolepsy

et al. 1997

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“…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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“…It is now known to be distributed widely in the CNS, with receptors reported to exist in structures such as the pituitary, cortex, brainstem, thalamus, hippocampus, amygdala, and spinal cord (see Griffiths and Bennett 1987;Jackson 1982;Metcalf 1982;Sharif 1985;and Winokur et al 1989 for reviews). Besides its role in stimulating the release of thyroid stimulating hormone (TSH) and prolactin (see Kolesnick and Gershengorn 1985 for a review), TRH has been shown to have various neuromodulating effects that are separate from its hormonal effects; it is known to have CNS stimulant and antidepressant effects, depolarize spinal motoneurons, and have various neurotrophic effects (see Griffiths and Bennett 1987;Jackson 1982;Metcalf 1982;Sharif 1985;and Winokur et al 1989 for reviews). Because of its CNS stimulant and antidepressant effects, TRH may be an attractive compound to study for possible use as treatment for narcolepsy.…”

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confidence: 99%

Chronic Oral Administration of CG-3703, a Thyrotropin Releasing Hormone Analog, Increases Wake and Decreases Cataplexy in Canine Narcolepsy

Riehl

Honda

Kwan

et al. 2000

Neuropsychopharmacology

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The effects on cataplexy and daytime sleep of acute and chronic oral administration of CG-3703, a potent TRH analog were assessed in canine narcolepsy. CG-3703 was found to be orally active and to reduce cataplexy (0.25 to 16 mg/kg) and sleep (8 and 16 mg/kg) in a dose-dependent manner. Two-week oral administration of Human narcolepsy is a chronic life-long disorder characterized by excessive daytime somnolence (EDS), abnormal manifestations of rapid eye movement (REM) sleep (hypnagogic hallucinations and sleep paralysis), and cataplexy (Aldrich 1992;Guilleminault 1994;. Cataplexy is a sudden loss of muscle tone in response to emotionally-exciting stimuli. It is akin to the muscle atonia that occurs during physiological REM sleep, but it occurs inappropriately during wakefulness (Aldrich 1992;Guilleminault 1994;. The current treatments for narcolepsy require the use of central nervous system (CNS) stimulants for EDS and antidepressants for cataplexy and abnormal REM sleep (Guilleminault 1994;Mitler et al. 1990;Thorpy and Goswami 1990). These treatments, however, are often unsatisfactory due to incomplete therapeutic efficacy, the occurrence of various side effects, and the rapid development of drug tolerance (Guilleminault 1994;Mitler et al. 1990;Thorpy and Goswami 1990). It is therefore necessary to explore more efficacious compounds with different pharmacological profiles for possible use in narcolepsy treatment.Canine narcolepsy is a naturally-occurring animal model of the human disorder. Like humans, narcoleptic canines exhibit short sleep latency, fragmented sleep patterns, and cataplexy (Kaitin et al. 1986;Nishino et al. 1998c;Riehl et al. 1998). Narcolepsy in Doberman pinschers and Labrador retrievers is caused by mutations in the gene encoding a receptor ( Hcrtr-2 ) for a novel neuropeptide, the hypocretins (orex- Received July 27, 1999; revised November 10, 1999; accepted December 23, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 23 , NO . 1 CG-3703, a TRH Analog, in Narcoleptic Dogs 35 ins) (Lin et al. 1999). Human and canine narcolepsy share similar pharmacological characteristics (see for a review). This model is thus an invaluable resource for the study of the pathophysiology and treatment of narcolepsy. To this end, the canine model has been used in numerous pharmacological experiments to dissect the mode of action of various compounds on their effects on wakefulness and cataplexy, and to screen new compounds for use as possible treatments for narcolepsy (see for a review).Thyrotropin releasing hormone (TRH) is a tripeptidic hormone (L-pyroglutamyl-L-histidyl-L-prolineamide) originally extracted from the hypothalamus (Boler et al. 1969). It is now known to be distributed widely in the CNS, with receptors reported to exist in structures such as the pituitary, cortex, brainstem, thalamus, hippocampus, amygdala, and spinal cord (see Griffiths and Bennett 1987;Jackson 1982;Metcalf 1982;Sharif 1985;and Winokur et al. 1989 for reviews). Besides its role in stimulating the release of thyroid stimul...

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Clinical applications of thyrotrophin-releasing hormone

Cited by 81 publications

References 0 publications

Effects of Thyrotropin-Releasing Hormone and Its Analogs on Daytime Sleepiness and Cataplexy in Canine Narcolepsy

Effects of Thyrotropin-Releasing Hormone and Its Analogs on Daytime Sleepiness and Cataplexy in Canine Narcolepsy

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

Chronic Oral Administration of CG-3703, a Thyrotropin Releasing Hormone Analog, Increases Wake and Decreases Cataplexy in Canine Narcolepsy

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