Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Effect of Orally Administered Relaxin in Experimental Nash

Version 1 : Received: 2 March 2020 / Approved: 3 March 2020 / Online: 3 March 2020 (11:16:49 CET)

How to cite: Colucci, G. Effect of Orally Administered Relaxin in Experimental Nash . Preprints 2020, 2020030037 (doi: 10.20944/preprints202003.0037.v1). Colucci, G. Effect of Orally Administered Relaxin in Experimental Nash . Preprints 2020, 2020030037 (doi: 10.20944/preprints202003.0037.v1).

Abstract

BACKGROUND Relaxin (RLX), a hormone-like molecule with pleiotropic effects, has been found to reduce matrix deposition and mediate collagen degradation in animal models of chronic liver injuries and might be considered as an adjuvant therapeutic agent for progressive liver diseases. AIMS In the present study, we evaluated whether RLX affects the development of liver fibrosis in an experimental mouse model of NASH in C57BL6 male mice fed with a methionine-choline deficient diet (MCD). Methods Mice were treated per os as we intended to assess the enteric absorption and bioavailability of orally administered RLX (RLX purified from pig ovaries, IBSA SA, Lugano, Switzerland). Mice were fed the MCD diet for 6 weeks. After the initial 3 weeks, one group received drinking water supplemented with RLX (25 mcg/ml) whereas the other continued to receive regular water. A third group of mice fed a regular diet served as control. After 3 additional weeks mice were anesthetized and sacrificed. Results A significant, reduced expression of the pro-inflammatory cytokines TNF-α and of relevant markers of active fibrogenesis and extracellular matrix deposition, Col1A1 and α-SMA, was observed in mice treated with RLX vs controls. RLX also induced a significant decrease of TIMP1 and an increase of both MMP 2 and 9 when evaluated by zymographic analysis in liver extracts. Conclusions Although preliminary pharmacokinetics experiments showed barely detectable amounts of RLX in the blood of mice treated per os, these data support the absorption of orally administered RLX and confirm its potential therapeutic use in the management of liver fibrosis.

Subject Areas

Extrac cellular matrix; Relaxin; liver fibrosis; MMPs

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