GSK-3β inhibitors attenuate the organ injury/dysfunction caused by endotoxemia in the rat*

Abstract

Objective: 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-3β inhibition on organ injury/dysfunction caused by lipopolysaccharide or coadministration of lipopolysaccharide and peptidoglycan in the rat. Design: Prospective, randomized study. Setting: University-based research laboratory. Subjects: Ninety-nine anesthetized male Wistar rats. Interventions: 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-3β 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. Measurements and Main Results: 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-3β inhibitors attenuated the organ injury/dysfunction caused by lipopolysaccharide or lipopolysaccharide and peptidoglycan. GSK-3β inhibition reduced the Ser536 phosphorylation of nuclear factor-κB subunit p65 and the messenger RNA expression of nuclear factor-κB-dependent proinflammatory mediators but had no effect on the nuclear factor-κB/DNA binding activity in the lung. GSK-3β inhibition reduced the increase in nuclear factor-κB p65 activity caused by interleukin-1 in human embryonic kidney cells in vitro. Conclusions: The potent and selective GSK-3β 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-3β 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.