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Berardo C

Berardo C

University of Pavia, Italy

Title: MPEP protection against hepatic ischemia/reperfusion injury is associated to TNF-α decrease

Biography

Biography: Berardo C

Abstract

The Negative Allosteric Modulator (NAM) 2-methyl-6-(phenylethynyl) pyridine (MPEP) of metabotropic Glutamate Receptor subtype 5 (mGluR5) improves viability of isolated anoxic hepatocytes1. It is known that during ischemia/reperfusion (I/R) injury, Kupffer cells activation occurs, causing an increase in TNF-α production. Moreover, TNF-α positively correlates with iNOS expression through NF-κB2,3 and because of the presence of TNF Response Element on iNOS gene4,5.

The aims of this study were: to investigate the protection mediated by other NAMs (MTEP and Fenoabam) against anoxic damage in isolated hepatocytes and to investigate the liver functionality in two ex vivo models of I/R.

Male Wistar rat hepatocytes were exposed to 90 minutes anoxia at 37°C with: MPEP and 3-((2-methyl-4-thiazolyl ethynyl pyridine (MTEP) at 3-30μM, Fenobam at 1-10-50-100μM. Hepatocytes viability was evaluated by trypan blue exclusion and LDH release. Wildtype and mGluR5 knockout livers from Balb-c mice were isolated, subjected to cold or normothermic I/R and treated with MPEP 0.3μM; transaminases release, BAX and Bcl-2, iNOS, eNOS and TNF-α protein expression were evaluated in cold I/R samples, while LDH, AST, TNF-α release were evaluated in normothermic samples.

MPEP 30μM, MTEP 3μM and Fenobam 50μM improved significantly anoxic isolated hepatocytes viability respect to anoxic controls. MPEP addition during I/R significantly reduced LDH, transaminases and TNF-alpha respect to ischemic controls in both cold and normothermic I/R, with a trend similar to mGluR5 knockout samples. Furthermore, MPEP reduced TNF-α levels, causing selectively iNOS expression decrease without affecting eNOS expression.

Our results demonstrated that MPEP, MTEP and Fenobam protect rat hepatocytes against ischemic injury. Furthermore, MPEP is able to reduce susceptibility of liver grafts to the preservation injury in two ex vivo models, in which the pharmacological blockade of mGluR5, interrupting the excitotoxic cascade, reduces the inflammation mediator TNF-α.