Javed, Muhammad Ahsan, Wen, Li, Awais, Muhammad, Latawiec, Diane, 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.
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TRO40303 Ameliorates Alcohol-Induced Pancreatitis Through Reduction of Fatty Acid Ethyl Ester-Induced Mitochondrial Injury and Necrotic Cell Death.pdf - Published version Download (378kB) | Preview |
Abstract
<h4>Objectives</h4>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).<h4>Methods</h4>Changes in mitochondrial membrane potential (Δψm), cytosolic Ca ([Ca]c), 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.<h4>Results</h4>TRO40303 prevented loss of Δψm 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.<h4>Conclusions</h4>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: | 14 Mar 2024 18:03 |
| DOI: | 10.1097/MPA.0000000000000953 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3043503 |
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