TRO40303 Ameliorates Alcohol-Induced Pancreatitis Through Reduction of Fatty Acid Ethyl Ester-Induced Mitochondrial Injury and Necrotic Cell Death


Javed, Muhammad Ahsan ORCID: 0000-0003-0402-2285, Wen, Li, Awais, Muhammad, Latawiec, Diane ORCID: 0000-0003-3097-9064, Huang, Wei, Chvanov, Michael, Schaller, Sophie, Bordet, Thierry, Michaud, Magali, Pruss, Rebecca et al (show 3 more authors) (2018) TRO40303 Ameliorates Alcohol-Induced Pancreatitis Through Reduction of Fatty Acid Ethyl Ester-Induced Mitochondrial Injury and Necrotic Cell Death PANCREAS, 47 (1). pp. 18-24. ISSN 0885-3177, 1536-4828

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Abstract

Objectives Mitochondrial permeability transition pore inhibition is a promising approach to treat acute pancreatitis (AP). We sought to determine (i) the effects of the mitochondrial permeability transition pore inhibitor 3,5-seco-4-nor-cholestan-5-one oxime-3-ol (TRO40303) on murine and human pancreatic acinar cell (PAC) injury induced by fatty acid ethyl esters (FAEEs) or taurolithocholic acid-3-sulfate and (ii) TRO40303 pharmacokinetics and efficacy in experimental alcoholic AP (FAEE-AP). Methods Changes in mitochondrial membrane potential (Δψ<inf>m</inf>), cytosolic Ca2+ ([Ca2+]<inf>c</inf>), and cell fate were examined in freshly isolated murine or human PACs by confocal microscopy. TRO40303 pharmacokinetics were assessed in cerulein-induced AP and therapeutic efficacy in FAEE-AP induced with palmitoleic acid and ethanol. Severity of AP was assessed by standard biomarkers and blinded histopathology. Results TRO40303 prevented loss of Δψ<inf>m</inf> and necrosis induced by 100 μM palmitoleic acid ethyl ester or 500 μM taurolithocholic acid-3-sulfate in murine and human PACs. Pharmacokinetic analysis found TRO40303 accumulated in the pancreas. A single dose of 3 mg/kg TRO40303 significantly reduced serum amylase (P = 0.043), pancreatic trypsin (P = 0.018), and histopathology scores (P = 0.0058) in FAEE-AP. Conclusions TRO40303 protects mitochondria and prevents necrotic cell death pathway activation in murine and human PACs, ameliorates the severity of FAEE-AP, and is a candidate drug for human AP.

Item Type: Article
Uncontrolled Keywords: alcohol, experimental acute pancreatitis, mitochondrial permeability transition pore (MPTP), necrosis, TRO40303
Depositing User: Symplectic Admin
Date Deposited: 29 May 2019 09:25
Last Modified: 16 Jun 2026 05:21
DOI: 10.1097/MPA.0000000000000953
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3043503
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