6-[(3-aminophenyl)methyl]-4-methyl-2-methylsulfinyl-5-thieno[3-4]pyrrolo[1-3-d]pyridazinone and Liver-Diseases

Accumulating evidence indicates that metabolic events profoundly modulate the progression of various diseases. Pyruvate is a central metabolic intermediate in glucose metabolism. In the present study, the metabolic status of pyruvate and its pharmacological significance has been investigated in mice with lipopolysaccharide/D-galactosamine (LPS/D-Gal)-induced fulminant liver injury. Our results indicated that LPS/D-Gal exposure decreased the activity of pyruvate kinase and the content of pyruvate, which were reversed by the PKM2 activator TEPP-46. Pretreatment with TEPP-46 or supplementation with the cell-permeable pyruvate derivate ethyl pyruvate (EP) attenuated LPS/D-Gal-induced liver damage. Interestingly, post-insult intervention of pyruvate metabolism also resulted in beneficial outcomes. The phospho-antibody microarray analysis and immunoblot analysis found that the inhibitory phosphorylation of cyclin dependent kinase 1 (CDK1) was reversed by TEPP-46, DASA-58 or EP. In addition, the therapeutic benefits of PKM2 activator or EP were blunted by the CDK1 inhibitor Ro 3306. Our data suggests that LPS/D-Gal exposure-induced decline of pyruvate might be a novel metabolic mechanism underlies the development of LPS/D-Gal-induced fulminant liver injury, PKM2 activator or pyruvate derivate might have potential value for the pharmacological intervention of fulminant liver injury.

Topics: Animals; Apoptosis; CDC2 Protein Kinase; Galactosamine; Hepatocytes; Lipopolysaccharides; Liver; Liver Diseases; Male; Mice; Mice, Inbred BALB C; Pyridazines; Pyrroles; Pyruvate Kinase; Pyruvates; Pyruvic Acid