Selective blockade of mGlu5 metabotropic glutamate receptors is hepatoprotective against fulminant hepatic failure induced by lipopolysaccharide and D-galactosamine in mice

This study was designed to investigate the influence of 2-methyl-6-phenylethynyl pyridine hydrochloride (MPEP), an antagonist of metabotropic glutamate receptor subtype 5, in lipopolysaccharide (LPS) and D-galactosamine (D-GaIN)-induced fulminant hepatic failure in mice. Mice were given an intraperitoneal injection of 50 mu g kg(-1) LPS and 500 mg kg(-1) D-GaIN. MPEP (1, 5 and 25 mg kg(-1)) was administered intraperitoneally 1 h before LPS/D-GaIN injection. Twenty-four hours after administration of LPS/D-GaIN, plasma was collected and used for biochemical assays. Mice were euthanized and histological analysis and toxicological parameters were carried out in the liver. MPEP, at all doses tested, protected against the increase in aspartate and alanine aminotransferase activities induced by LPS/D-GaIN exposure. Ascorbic acid levels were not altered in all experimental groups. Glutathione S-transferase activity was increased by administration of LPS/D-GaIN and MPEP did not modify the enzyme activity in mice. MPEP, at the doses of 5 and 25 mg kg(-1), was effective in protecting against the decrease in catalase activity caused by LPS/D-GaIN administration in mice. The histological data showed that sections of liver from LPS/D-GaIN-exposed mice presented extensive injuries. MPEP, at all doses tested, reduced the scores of liver damage and markedly ameliorated the degree of liver damage. The hepatoprotective effect of MPEP on fulminant hepatic failure induced by LPS and D-GaIN in mice was demonstrated. Copyright (C) 2009 John Wiley & Sons, Ltd.