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Int. J. Mol. Sci. 2018, 19(2), 314; https://doi.org/10.3390/ijms19020314

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

1
Department of Internal Medicine and Therapeutics, Cellular and Molecular Pharmacology and Toxicology Unit, University of Pavia, 27100 Pavia, Italy
2
Department of Physiology and Pharmacology, Sapienza University, 00185 Roma, Italy
3
I.R.C.C.S. Neuromed, 86077 Pozzilli, Italy
*
Author to whom correspondence should be addressed.
Received: 20 November 2017 / Revised: 18 January 2018 / Accepted: 22 January 2018 / Published: 23 January 2018
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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. View Full-Text
Keywords: mGluR5; MPEP; MTEP; fenobam; ischemia; liver; mice; liver transplantation; mitochondria; hepatocytes mGluR5; MPEP; MTEP; fenobam; ischemia; liver; mice; liver transplantation; mitochondria; hepatocytes
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Ferrigno, A.; Berardo, C.; Di Pasqua, L.G.; Siciliano, V.; Richelmi, P.; Nicoletti, F.; Vairetti, M. Selective Blockade of the Metabotropic Glutamate Receptor mGluR5 Protects Mouse Livers in In Vitro and Ex Vivo Models of Ischemia Reperfusion Injury. Int. J. Mol. Sci. 2018, 19, 314.

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