sb-415286 and Endotoxemia

The serine-threonine protein kinase glycogen synthase kinase (GSK)-3 is involved in the regulation of many cell functions, but its role in the regulation of the inflammatory response is unknown. Here we investigate the effects of GSK-3beta inhibition on organ injury/dysfunction caused by endotoxaemia or severe inflammation in the rat. Rats received either intravenous Escherichia coli lipopolysaccharide (LPS) (6 mg/kg) or LPS (1mg/kg) plus Staphylococcus aureus peptidoglycan (PepG) (0.3mg/kg) or their vehicle (saline). The GSK-3p1 inhibitors TDZD-8, SB415286 (both 1mg/kg, i.v.), and SB216763 (0.6 mg/kg i.v.), or vehicle (10% dimethyl sulfoxide) were administered 30 min before LPS or LPS/PepG. Both endotoxaemia and co-administration of LPS/PepG resulted in multiple organ injury and dysfunction. The GSK-3beta inhibitors attenuated the organ injury/dysfunction caused by LPS or LPS/PepG. GSK-3beta inhibition reduced the Ser536 phosphorylation of nuclear factor (NF)-kappaB subunit p65 and the mRNA expression of NF-kappaB-dependent pro-inflammatory mediators, but had no effect on the NF-kappaB/DNA binding activity in the lung. GSK-3beta inhibition reduced the increase in NF-kappaB p65 activity caused by interleukin (IL)1 in human e mbryonic kidney cells in vitro. We propose that GSK-3beta inhibition may be useful in the therapy of sepsis, shock and other diseases associated with local or systemic inflammation.

Topics: Alanine Transaminase; Aminophenols; Animals; Aspartate Aminotransferases; Blotting, Western; Cells, Cultured; Creatinine; Endotoxemia; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Indoles; Interleukin-1beta; Kidney; Lipopolysaccharides; Male; Maleimides; Peptidoglycan; Phosphorylation; Rats; Rats, Wistar; Sepsis; Thiadiazoles; Transcription Factor RelA

Serine-threonine protein kinase glycogen synthase kinase (GSK)-3 is involved in regulation of many cell functions, but its role in regulation of inflammatory response is unknown. Here we investigate the effects of GSK-3beta inhibition on organ injury/dysfunction caused by lipopolysaccharide or coadministration of lipopolysaccharide and peptidoglycan in the rat.. Prospective, randomized study.. University-based research laboratory.. Ninety-nine anesthetized male Wistar rats.. Study 1: Rats received either intravenous Escherichia coli lipopolysaccharide (6 mg/kg) or vehicle (1 mL/kg; saline). Study 2: Rats received either intravenous E. coli lipopolysaccharide (1 mg/kg) and Staphylococcus aureus peptidoglycan (0.3 mg/kg) or vehicle. The potent and selective GSK-3beta inhibitors TDZD-8 (1 mg/kg intravenously), SB216763 (0.6 mg/kg intravenously), and SB415286 (1 mg/kg intravenously) or vehicle (10% dimethyl sulfoxide) was administered 30 mins before lipopolysaccharide or lipopolysaccharide and peptidoglycan.. Endotoxemia resulted in increases in the serum levels of creatinine (indicator of renal dysfunction), aspartate aminotransferase, alanine aminotransferase (markers for hepatocellular injury), lipase (indicator of pancreatic injury), and creatine kinase (indicator of neuromuscular injury). Coadministration of lipopolysaccharide and peptidoglycan resulted in hepatocellular injury and renal dysfunction. All GSK-3beta inhibitors attenuated the organ injury/dysfunction caused by lipopolysaccharide or lipopolysaccharide and peptidoglycan. GSK-3beta inhibition reduced the Ser536 phosphorylation of nuclear factor-kappaB subunit p65 and the messenger RNA expression of nuclear factor-kappaB-dependent proinflammatory mediators but had no effect on the nuclear factor-kappaB/DNA binding activity in the lung. GSK-3beta inhibition reduced the increase in nuclear factor-kappaB p65 activity caused by interleukin-1 in human embryonic kidney cells in vitro.. The potent and selective GSK-3beta inhibitors TDZD-8, SB216763, and SB415286 reduced the organ injury/dysfunction caused by lipopolysaccharide or lipopolysaccharide and peptidoglycan in the rat. We propose that GSK-3beta inhibition may be useful in the therapy of the organ injury/dysfunction associated with sepsis, shock, and other diseases associated with local or systemic inflammation.

Topics: Alanine Transaminase; Aminophenols; Animals; Aspartate Aminotransferases; Blotting, Western; Cells, Cultured; Creatine Kinase; Creatinine; Endotoxemia; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Indoles; Kidney Diseases; Lipase; Lipopolysaccharides; Liver; Male; Maleimides; NF-kappa B; Peptidoglycan; Phosphorylation; Polysaccharides, Bacterial; Prospective Studies; Random Allocation; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Thiadiazoles