Selective Blockade of the Metabotropic Glutamate Receptor mGluR5 Protects Mouse Livers in In Vitro and Ex Vivo Models of Ischemia Reperfusion Injury

Andrea Ferrigno, Clarissa Berardo, Laura Giuseppina Di Pasqua, Veronica Siciliano, Plinio Richelmi, Ferdinando Nicoletti, Mariapia Vairetti

Research output: Contribution to journalArticlepeer-review

Abstract

2-Methyl-6-(phenylethynyl)pyridine (MPEP), a negative allosteric modulator of the metabotropic glutamate receptor (mGluR) 5, protects hepatocytes from ischemic injury. In astrocytes and microglia, MPEP depletes ATP. These findings seem to be self-contradictory, since ATP depletion is a fundamental stressor in ischemia. This study attempted to reconstruct the mechanism of MPEP-mediated ATP depletion and the consequences of ATP depletion on protection against ischemic injury. We compared the effects of MPEP and other mGluR5 negative modulators on ATP concentration when measured in rat hepatocytes and acellular solutions. We also evaluated the effects of mGluR5 blockade on viability in rat hepatocytes exposed to hypoxia. Furthermore, we studied the effects of MPEP treatment on mouse livers subjected to cold ischemia and warm ischemia reperfusion. We found that MPEP and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) deplete ATP in hepatocytes and acellular solutions, unlike fenobam. This finding suggests that mGluR5s may not be involved, contrary to previous reports. MPEP, as well as MTEP and fenobam, improved hypoxic hepatocyte viability, suggesting that protection against ischemic injury is independent of ATP depletion. Significantly, MPEP protected mouse livers in two different ex vivo models of ischemia reperfusion injury, suggesting its possible protective deployment in the treatment of hepatic inflammatory conditions.

Original languageEnglish
Article numbere314
JournalInternational Journal of Molecular Sciences
Volume19
Issue number2
DOIs
Publication statusPublished - Jan 23 2018

Keywords

  • Adenosine Triphosphate/metabolism
  • Animals
  • Cell Hypoxia/drug effects
  • Disease Models, Animal
  • Hepatocytes/drug effects
  • Imidazoles/pharmacology
  • Liver/blood supply
  • Mice
  • Mitochondria, Liver/drug effects
  • Piperidines/pharmacology
  • Pyridines/pharmacology
  • Rats
  • Receptor, Metabotropic Glutamate 5/antagonists & inhibitors
  • Reperfusion Injury/metabolism
  • Thiazoles/pharmacology
  • Tumor Necrosis Factor-alpha/metabolism

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