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

Kelly, Julie; Boyle, Noreen T.; Cole, Natalie; Slator, Gillian R.; Colivicchi, Maria Alessandra; Stefanini, Chiara; Gobbo, Oliviero L.; Scalabrino, Gaia; Ryan, Sinéad M.; Elamin, Marwa; Walsh, Cathal; Vajda, Alice; Goggin, Margaret M.; Campbell, Matthew; Mash, Deborah C.; O’Mara, Shane M.; Brayden, David J.; Callanan, John J.; Tipton, Keith F.; Corte, Laura Della; Hunter, Jackie; O’Boyle, Kathy M.; Williams, C. H.; Hardiman, Orla

doi:10.1016/j.neuropharm.2014.09.024

Cited by 22 publications

(20 citation statements)

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“…They noted that these receptors are pharmacologically distinct from TRH receptors in human pituitary, thus providing the possibility of a new TRH receptor subtype. 25 It is possible that the inconsistent effects of administered TRH and its analogues in humans may have been caused by their rapid degradation of and poor blood-brain barrier penetration. 26 …”

Section: Resultsmentioning

confidence: 99%

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Discovery of a low affinity thyrotropin-releasing hormone (TRH)-like peptide that exhibits potent inhibition of scopolamine-induced memory impairment in mice

et al. 2015

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TRH-like peptides were synthesized in which the critical N-terminus residue L-pGlu was replaced with various heteroaromatic rings, and the central residue histidine with 1-alkyl-L-histidines. All synthesized TRH-like peptides were evaluated in vitro as agonists in HEK mTRH-R1 and HEK mTRH-R2 cell lines, an expressing receptor binding assay (IC50), and cell signaling assay (EC50). The analeptic potential of the synthesized peptides was evaluated in vivo by using the antagonism of a pentobarbital-induced sleeping time. The peptides 6a, 6c and 6e were found to activate TRH-R2 with potencies (EC50) of 0.002 μM, 0.28 μM and 0.049 μM, respectively. In contrast, for signaling activation of TRH-R1, the same peptides required higher concentration of 0.414 μM, 50 μM and 19.1 μM, respectively in the FLIPR assay. The results showed that these peptides were 207, 178 and 389-fold selective towards TRH-R2 receptor subtype. In the antagonism of a pentobarbital-induced sleeping time assay, peptide 6c showed a 58.5% reduction in sleeping time. The peptide 6c exhibited high stability in rat blood plasma, a superior effect on the scopolamine-induced cognition impairment mice model, safe effects on the cardiovascular system, and general behavior using a functional observation battery (FOB).

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Section: Resultsmentioning

confidence: 99%

“…It may be noted that earlier studies indicated the possibility that novel TRH receptors may mediate the CNS actions of TRH-like peptides, and it can be postulated that the CNS effects of the peptides reported herein may be mediated through such a novel TRH receptor subtype. 23–25 …”

Section: Resultsmentioning

confidence: 99%

Discovery of a low affinity thyrotropin-releasing hormone (TRH)-like peptide that exhibits potent inhibition of scopolamine-induced memory impairment in mice

et al. 2015

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“…The regulatory mechanism, in mammals, is that stimulated hypothalamic secretes TRH and works on the pituitary, binding of TRH to TRHR on the surface of pituitary gland cells, to increase synthesis and the release of TSH [32,33]. The TSH acts on the thyroid by interacting with TSHR to promote the secretion of THs [34,35].…”

Section: Discussionmentioning

confidence: 99%

Correction and Republication: Effect of Di-(2-ethylhexyl) phthalate on the hypothalamus-pituitary-thyroid axis in adolescent rat

et al. 2018

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Abstract. Di-(2-ethylhexyl) phthalate (DEHP) is extensively used in many personal care and consumer products, which has resulted in widespread human exposure. Limited studies have suggested that exposure to DEHP may affect thyroid function, but little is known about the effect and mechanisms of DEHP exposure on the hypothalamic-pituitary-thyroid axis (HPTA). The present study was conducted to elucidate the potential mechanisms in which DEHP disrupts the function of the HPTA. Wistar rats were administered DEHP by gavage at 0, 5, 50, and 500 mg/kg/day for 28 days and then sacrificed within 24 h following the last dose. Hormones of HPTA was quantified with radioimmunoassay and enzyme-linked immunosorbent assay, protein levels of thyrotropin-releasing hormone receptor (TRHR) and thyroid-stimulating hormone receptor (TSHR) were analyzed by Western blot and immunohistochemistry, expression levels of TRHR and TSHR mRNA were measured by quantitative real-time PCR. Rats treated with DEHP resulted in increased bodyweight, on the HPTA, down-regulated the protein levels of TRH in the hypothalamus, up-regulated the protein and mRNA levels of TRHR in the pituitary, downregulated mRNA expression of TSHR in the thyroid, while the difference of TSH in various dose groups was not statistically significant and T3, T4, FT3, FT4 levels in serum were decreased compared with control. DEHP could interfere with the balance of HPTA of adolescent rats, and increase the body weight, down-regulate the homeostasis of thyroid related hormones and receptors expression levels. Correspondence to: Lin Ye, Department of Occupational and Environmental Health, School of Public Health, Jilin University, 1163 Xin Min Street, Changchun, 130021, China. E-mail: jlyelin@163.com *These authors equally contributed to this work. Abbreviations: DEHP, Di-(2-ethylhexyl) phthalate; EEDs, environmental endocrine disruptors; HPTA, hypothalamic-pituitary-thyroid axis; MEHP, mono-(2-ethylhexyl) phthalate; PAEs, Phthalic acid esters; PVC, polyvinyl chloride; QPCR, quantitative real-time PCR; THs, thyroid hormones; TRH, thyrotropin-releasing hormone; TRHR, thyrotropin-releasing hormone receptor; TSH, thyroidstimulating hormone; TSHR, thyroid-stimulating hormone receptor ambient air, water sources, and sediments [5][6][7]. Human exposure to PAEs mainly occurs through food due to the use of PVC in wrapping materials and food processing [1,8]. Once ingested through food contamination, di-(2-ethylhexyl) phthalate (DEHP), one of the most widely used and studied phthalates esters, is quickly metabolized to its monoester equivalent mono-(2-ethylhexyl) phthalate] (MEHP), which is preferentially absorbed [9,10]. The biological effects of MEHP are hence of major concern; however, gaining an understanding of the underlying mechanistic events has posed several challenges. In the past, researches about DEHP mainly focused on reproductive defects [11][12][13]. More recently, greater attention has been paid on the thyroid toxic of DEHP.The thyroid is the largest endocrine organ in h...

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“…There is some evidence for efficacy of this TRH analogue in the treatment of spinocerebellar ataxia and other neurodegenerative disorders [36,37]. A new TRH analogue with potential for oral delivery is in preclinical development targeting neurodegenerative conditions [38].…”

Section: Oral Peptides That Are Systemically Absorbedmentioning

confidence: 99%

Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials

Aguirre

Teijeiro‐Osorio

Rosa

et al. 2016

Advanced Drug Delivery Reviews

252

151

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Publication informationAdvanced Drug Delivery Reviews, 106 (Part B):Publisher Elsevier Item record/more information http://hdl.handle.net/10197/7801 Publisher's statementThis is the author's version of a work that was accepted for publication in Advanced Drug Delivery Reviews. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Advanced Drug Delivery Reviews (106, Part B, (2016)

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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

Cited by 22 publications

References 72 publications

Discovery of a low affinity thyrotropin-releasing hormone (TRH)-like peptide that exhibits potent inhibition of scopolamine-induced memory impairment in mice

Discovery of a low affinity thyrotropin-releasing hormone (TRH)-like peptide that exhibits potent inhibition of scopolamine-induced memory impairment in mice

Correction and Republication: Effect of Di-(2-ethylhexyl) phthalate on the hypothalamus-pituitary-thyroid axis in adolescent rat

Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials

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