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-GalN)-induced fulminant hepatic failure in mice. Mice were given an intraperitoneal injection of 50 microg kg(-1) LPS and 500 mg kg(-1) D-GalN. MPEP (1, 5 and 25 mg kg(-1)) was administered intraperitoneally 1 h before LPS/D-GalN injection. Twenty-four hours after administration of LPS/D-GalN, 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-GalN exposure. Ascorbic acid levels were not altered in all experimental groups. Glutathione S-transferase activity was increased by administration of LPS/D-GalN 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-GalN administration in mice. The histological data showed that sections of liver from LPS/D-GalN-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-GalN in mice was demonstrated.
Jesse
Cristiano R
CR
Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, RS, Brazil.
Wilhelm
Ethel A
EA
Bortolatto
Cristiani F
CF
Savegnago
Lucielli
L
Nogueira
Cristina W
CW
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000097:blood; D002374:Catalase / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D005688:Galactosamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D005982:Glutathione Transferase / Q000378:metabolism; D007274:Injections, Intraperitoneal; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D017114:Liver Failure, Acute / Q000473:pathology* / Q000517:prevention & control*; D051379:Mice; D020011:Protective Agents; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D016019:Survival Analysis
D018691:Excitatory Amino Acid Antagonists; D008070:Lipopolysaccharides; D020011:Protective Agents; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D005688:Galactosamine; C121465:6-methyl-2-(phenylethynyl)pyridine; D002374:Catalase; D005982:Glutathione Transferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001205:Ascorbic Acid