GSK-3beta inhibitors attenuate the organ injury/dysfunction caused by endotoxemia in the rat.
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-3beta inhibition on organ injury/dysfunction caused by lipopolysaccharide or coadministration of lipopolysaccharide and peptidoglycan in the rat.


METHODS
Prospective, randomized study.


METHODS
University-based research laboratory.


METHODS
Ninety-nine anesthetized male Wistar rats.


METHODS
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.


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-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.


CONCLUSIONS
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.
Dugo
Laura
L
Centre for Experimental Medicine, Nephrology and Critical Care Medicine, The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Charterhouse Square, London, UK.
Collin
Marika
M
Allen
David A
DA
Patel
Nimesh S A
NS
Bauer
Inge
I
Mervaala
Eero M A
EM
Louhelainen
Marjut
M
Foster
Simon J
SJ
Yaqoob
Muhammad M
MM
Thiemermann
Christoph
C
D000410:Alanine Transaminase / Q000097:blood; D000627:Aminophenols / Q000008:administration & dosage; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000097:blood; D003404:Creatinine / Q000097:blood; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use; D007674:Kidney Diseases / Q000139:chemically induced; D008049:Lipase / Q000097:blood; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008099:Liver / Q000473:pathology; D008297:Male; D008301:Maleimides / Q000008:administration & dosage / Q000627:therapeutic use; D016328:NF-kappa B / Q000378:metabolism; D010457:Peptidoglycan / Q000008:administration & dosage; D010766:Phosphorylation; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage; D011446:Prospective Studies; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013830:Thiadiazoles / Q000008:administration & dosage / Q000627:therapeutic use*
C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D000627:Aminophenols; D007211:Indoles; D008070:Lipopolysaccharides; D008301:Maleimides; D016328:NF-kappa B; D010457:Peptidoglycan; D011135:Polysaccharides, Bacterial; C417521:SB 216763; D013830:Thiadiazoles; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D003402:Creatine Kinase; D008049:Lipase