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1-Methyl tryptophan, an indoleamine 2,3-dioxygenase inhibitor, attenuates cardiac and hepatic dysfunction in rats with biliary cirrhosis

Shayesteh, S; Guillemin, GJ; Rashidian, A; Faghir-Ghanesefat, H; Mani, AR; Tavangar, SM; Dehpour, AR; (2021) 1-Methyl tryptophan, an indoleamine 2,3-dioxygenase inhibitor, attenuates cardiac and hepatic dysfunction in rats with biliary cirrhosis. European Journal of Pharmacology , 908 , Article 174309. 10.1016/j.ejphar.2021.174309.

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Abstract

Kynurenine Pathway (KP) is the dominant metabolic route of tryptophan which is catalyzed by indoleamine-2,3-dioxygenase (IDO). This pathway is upregulated in liver disease where the level of KP metabolites correlates with the severity of disease. Cirrhosis is associated with cardiac dysfunction, which manifests itself during severe physiological challenges such as liver transplantation. Cardiac dysfunction in cirrhosis is linked to systemic inflammation and impaired cardiac beta-adrenergic signaling pathways. The KP pathway is involved in modulation of cardiac signaling and is upregulated by systemic inflammation. Therefore, this study aimed to evaluate the effect of IDO inhibition on development of cardiac dysfunction in an experimental model of cirrhosis. Cirrhosis was induced by bile duct ligation (BDL). Experimental groups were given either 1-methyl tryptophan (1-MT, 1, 3, 9 mg/kg), or saline. 28 days after BDL, cardiac chronotropic response to epinephrine was assessed ex vivo. HPLC was employed to measure hepatic and cardiac levels of tryptophan, kynurenine and kynurenic acid. Cirrhosis in rats was associated with impaired cardiac chronotropic responsiveness to adrenergic stimulation. 1-MT dose-dependently improved cirrhosis-induced chronotropic dysfunction as well as elevated serum levels of CRP and IL-6 in BDL rats. Hepatic and cardiac kynurenine/tryptophan ratio were elevated in cirrhotic rats and were reduced following 1-MT administration. Chronic administration of 1-MT could also reduce hepatic inflammation, fibrosis and ductular proliferation. 1-MT attenuates cardiac dysfunction in rats with biliary cirrhosis. This protective effect is not limited to the cardiac function as liver histopathologic changes were also improved following chronic 1-MT administration.

Type: Article
Title: 1-Methyl tryptophan, an indoleamine 2,3-dioxygenase inhibitor, attenuates cardiac and hepatic dysfunction in rats with biliary cirrhosis
Location: Netherlands
DOI: 10.1016/j.ejphar.2021.174309
Publisher version: https://doi.org/10.1016/j.ejphar.2021.174309
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: 1-Methyl tryptophan, Cardiomyopathy, Cirrhosis, Indoleamine-2,3-dioxygenase, Kynurenine, Tryptophan
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Department of Education
URI: https://discovery.ucl.ac.uk/id/eprint/10131670
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