Date: Sunday, October 21, 2018
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Serotonin or 5-hydroxytryptamine (5-HT) is well known as a stimulator of tissue fibrosis and a significant role of peripheral 5-HT2B receptors in fibrosis has been suggested with the receptor being upregulated in fibrotic tissues. In addition, agonism of the 5-HT2B receptor has been implicated in human tissue fibrosis caused by drugs known to activate the receptor. Pharmacologic inhibition of 5-HT2B receptor signalling consequently represents a promising treatment strategy for fibrotic disorders including systemic sclerosis. 5-HT is released from platelets activated due to vascular damage, one of the first pathological events in systemic sclerosis. The local 5-HT concentration is increased and leads to activation of 5-HT2B receptors on e.g. fibroblasts. This results in progression of myofibroblast differentiation leading to excessive extracellular matrix synthesis and eventually fibrosis. The objective of the present study was to evaluate a novel highly selective orally available 5-HT2B receptor antagonist for its ability to reduce pulmonary and dermal fibrosis in the sclerodermatous chronic graft-versus-host disease model and dermal fibrosis in the tight-skin-1 model of systemic sclerosis.
The murine sclerodermatous chronic graft-versus-host disease (cGvHD) model was used to evaluate anti-fibrotic effects after therapeutic dosing of the 5-HT2B receptor antagonist, AM1476. The compound was orally administered at 1, 10 and 30 mg/kg b.i.d. from day 21, several days after the first clinical signs of cGvHD, to day 49. Dermal thickness, myofibroblast counts, collagen production and number of phosphorylated Smad3 positive cells were used to evaluate dermal fibrosis. Effects on pulmonary fibrosis were measured using hydroxyproline content, Sirius Red staining and Ashcroft score. The tight-skin-1 model was used to evaluate anti-fibrotic effects after therapeutic treatment. AM1476 was orally administered at 10 mg/kg, b.i.d. from week 5 to week 10. Hypodermal thickening, myofibroblast counts and hydroxyproline content in skin biopsies were evaluated at the end of the treatment period.
The 5-HT2B receptor antagonist AM1476, significantly reduced all measured dermal and pulmonary fibrosis readouts in the cGvHD model using an oral therapeutic treatment approach. Therapeutic treatment of dermal fibrosis in the tight-skin model effectively and significantly reduced hypodermal thickening, number of myofibroblast and hydroxyproline content.
Inhibition of 5-HT2B receptor activity resulted in pronounced anti-fibrotic effects in both pulmonary and dermal fibrotic tissues. The highly selective 5-HT2B receptor antagonist AM1476 represents a promising drug candidate for treatment of fibrotic conditions and is currently in development for systemic sclerosis.
To cite this abstract in AMA style:Wenglén C, Arozenius H, Pettersson L, Ekström G. An Orally Available Highly Selective 5-Hydroxytryptamine 2B Receptor Antagonist Ameliorating Pulmonary and Dermal Fibrosis in Preclinical Models of Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/an-orally-available-highly-selective-5-hydroxytryptamine-2b-receptor-antagonist-ameliorating-pulmonary-and-dermal-fibrosis-in-preclinical-models-of-systemic-sclerosis/. Accessed November 26, 2022.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/an-orally-available-highly-selective-5-hydroxytryptamine-2b-receptor-antagonist-ameliorating-pulmonary-and-dermal-fibrosis-in-preclinical-models-of-systemic-sclerosis/