Metabotropic Glutamate Receptor Blockade Reduces Preservation Damage in Livers from Donors after Cardiac Death
Open Access
- 24 February 2021
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 22 (5), 2234
- https://doi.org/10.3390/ijms22052234
Abstract
We previously demonstrated that the blockade of mGluR5 by 2-methyl-6(phenylethynyl)pyridine (MPEP) reduces both cold and warm ischemia/reperfusion injury. Here we evaluated whether MPEP reduces the hepatic preservation injury in rat livers from cardiac-death-donors (DCDs). Livers from DCD rats were isolated after an in situ warm ischemia (30 min) and preserved for 22 h at 4 °C with UW solution. Next, 10 mg/Kg MPEP or vehicle were administered 30 min before the portal clamping and added to the UW solution (3 µM). LDH released during washout was quantified. Liver samples were collected for iNOS, eNOS, NO, TNF-α, ICAM-1, caspase-3 and caspase-9 protein expression and nuclear factor-erythroid-2-related factor-2 (Nrf2) gene analysis. Lower LDH levels were detected in control grafts versus DCD groups. An increase in eNOS and NO content occurred after MPEP treatment; iNOS and TNF-α content was unchanged. ICAM-1 expression was reduced in the MPEP-treated livers as well as the levels of caspase-3 and caspase-9. Nrf2, oxidative stress-sensitive gene, was recovered to control value by MPEP. These results suggest that MPEP can be used to reclaim DCD livers subjected to an additional period of cold ischemia during hypothermic storage. MPEP protects against apoptosis and increased eNOS, whose overexpression has been previously demonstrated to be protective in hepatic ischemia/reperfusion damage.Funding Information
- Funds from the University of Pavia and the University of Turin (Ricerca Locale 2019)
This publication has 39 references indexed in Scilit:
- Liver transplantation from brain‐dead donors on mechanical circulatory support: a systematic review of the literatureTransplant International, 2020
- Using Marginal Grafts for Liver Transplantation: The Balance of RiskJournal of Investigative Surgery, 2019
- Liver Transplantation Today: Where We Are Now and Where We Are GoingLiver Transplantation, 2018
- The need and opportunity for donation after circulatory death worldwideCurrent Opinion in Organ Transplantation, 2018
- Selective Blockade of the Metabotropic Glutamate Receptor mGluR5 Protects Mouse Livers in In Vitro and Ex Vivo Models of Ischemia Reperfusion InjuryInternational Journal of Molecular Sciences, 2018
- Localization and role of metabotropic glutamate receptors subtype 5 in the gastrointestinal tract.World Journal of Gastroenterology, 2017
- Perioperative complications in liver transplantation using donation after cardiac death grafts: A propensity-matched studyLiver Transplantation, 2014
- Mouse hepatocytes lacking mGlu5 metabotropic glutamate receptors are less sensitive to hypoxic damageEuropean Journal of Pharmacology, 2004
- Selective blockade of mGlu5 metabotropic glutamate receptors is protective against acetaminophen hepatotoxicity in miceJournal of Hepatology, 2003
- Selective blockade of mGlu5 metabotropic glutamate receptors protects rat hepatocytes against hypoxic damageHepatology, 2000