Background
Emricasan is a pan-caspase inhibitor.1,2,3,4 Ex vivo, emricasan (10 mg/kg) prevents cold ischemia-warm reperfusion-induced sinusoidal endothelial cell (SEC) apoptosis and inhibits caspase-3 activation in rat liver by 55 and 94%, respectively.1 In vivo, emricasan reduces alanine aminotransferase (ALT) levels (ED50s = <0.01-0.38 mg/kg) as well as apoptosis and caspase activity in a dose-dependent manner in the α-Fas mouse and D-Gln/LPS rat models of liver injury.2 Emricasan reduces caspase-3 and caspase-8 activity, serum ALT levels, hepatocyte apoptosis, and hepatic fibrogenesis in a mouse model of high-fat diet-induced non-alcoholic steatohepatitis (NASH).3 It also enhances islet engraftment and lowers post-transplant fasting glucose levels in a porcine islet autotransplant model.4
1.Natori, S., Higuchi, H., Contreras, P., et al.The caspase inhibitor IDN-6556 prevents caspase activation and apoptosis in sinusoidal endothelial cells during liver preservation injuryLiver Transpl.9(3)278-284(2003)
2.Hoglen, N.C., Chen, L.S., Fisher, C.D., et al.Characterization of IDN-6556 (3-[2-(2-tert-butyl-phenylaminooxalyl)-amino]-propionylamino]-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid): A liver-targeted caspase inhibitorJ. Pharmacol. Exp. Ther.309(2)634-640(2004)
3.Barreyro, F.J., Holod, S., Finocchietto, P.V., et al.The pan-caspase inhibitor emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitisLiver Int.35(3)953-966(2015)
4.McCall, M.D., Maciver, A.M., Kin, T., et al.Caspase inhibitor IDN6556 facilitates marginal mass islet engraftment in a porcine islet autotransplant modelTransplantation94(1)30-35(2012)
Protocol
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Animal experiment:
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Mice[2] The male C57BL/6J mice are age-matched and used at approximately 12-16 weeks of age. Four groups are studied (n=60) with 15 mice per group. Groups 1 and 3 receive regular chow. Groups 2 and 4 receive HFD and 50 g/L (Sucrose) is added to drinking water for 20 weeks. Groups 3 and 4 receive Emricasan 0.3 mg/kg/day per os, and Group 1 and 2 receive the vehicle. The oral administration of Emricasan at doses of 0.3 mg/kg corresponds to the ED90 value to prevent liver injury in the model of α-Fas-induced liver injury. Total body weight is measured at 0, 5, 10, 15 and 20 weeks. Rats[3] The male Sprague-Dawley rats are cannulated in the carotid artery under isoflurane anesthesia and allowed to recover for at least 1 day before drug administration. Blood (100 μL/sample) is taken from the carotid cannula 2 to 240 min after administration of Emricasan (i.v., s.c., p.o., or i.p.). Serum is prepared and frozen immediately until analysis. In studies measuring drug concentrations in portal and systemic blood, individual rats are bled (three animals per time point) simultaneously from the portal vein and inferior vena cava. In the biliary excretion study, bile is collected from the common bile duct after i.v. and p.o. administration of Emricasan (10 mg/kg) over a 24-h period on ice and frozen until analysis.
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参考文献:
[1]. Gracia-Sancho J, et al. Emricasan Ameliorates Portal Hypertension and Liver Fibrosis in Cirrhotic Rats Through a Hepatocyte-Mediated Paracrine Mechanism. Hepatol Commun. 2019 Apr 22;3(7):987-1000.
[2]. Barreyro FJ, et al. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int. 2015 Mar;35(3):953-66.
[3]. Hoglen NC, et al. Characterization of IDN-6556 (3-[2-(2-tert-butyl-phenylaminooxalyl)-amino]-propionylamino]-4-oxo-5-(2,3,5,6-te trafluoro-phenoxy)-pentanoic acid): a liver-targeted caspase inhibitor. J Pharmacol Exp Ther. 2004 May;309(2):634-40.
[4]. McCall M, et al. The caspase inhibitor IDN-6556 (PF3491390) improves marginal mass engraftment after islet transplantation in mice. Surgery. 2011 Jul;150(1):48-55.
[5]. Tian J, et al. Combination of Emricasan with Ponatinib Synergistically Reduces Ischemia/Reperfusion Injury in Rat Brain Through Simultaneous Prevention of Apoptosis and Necroptosis. Transl Stroke Res. 2017 Nov 4.
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