Reduction of experimental colitis in the rat by inhibitors of glycogen synthase kinase-3beta.
The effects of the inhibitors of glycogen synthase kinase-3beta (GSK-3beta), TDZD-8 and SB 415286, which can substantially reduce the systemic inflammation associated with endotoxic shock in vivo, have now been investigated on the acute colitis provoked by trinitrobenzene sulphonic acid (TNBS) in the rat. Administration of the GSK-3beta inhibitor TDZD-8 (0.1, 0.33 or 1.0 mg kg-1, s.c., b.i.d., for 3 days) caused a dose-dependent reduction in the colonic inflammation induced by intracolonic TNBS assessed after 3 days, both as the area of macroscopic involvement and as a score using 0-10 scale. Likewise, following administration of the GSK-3beta inhibitor SB 415286 (0.1, 0.33 or 1.0 mg kg-1, s.c., b.i.d., for 3 days), the extent and degree of the TNBS-provoked colonic inflammation was reduced. Administration of either TDZD-8 or SB 415286 reduced the fall in body weight following challenge with TNBS at each dose level studied. The increase in myeloperoxidase activity, an index of neutrophil infiltration into the TNBS-induced inflamed colon, was significantly inhibited by both TDZD-8 and SB 415286 at each dose level. The increase in the levels of the proinflammatory cytokine, TNF-alpha, in the inflamed colon was also significantly inhibited by either compound at the highest doses evaluated. The elevated levels of the transcription factor NF-kappaB subunit p65, as determined by Western blot in the nuclear extracts from the TNBS-provoked inflamed colonic tissue, were dose-dependently reduced by TDZD-8 or SB 415286 treatment. These findings demonstrate that two chemically distinct selective inhibitors of the activity of GSK-3beta reduce the inflammation and tissue injury in a rat model of acute colitis. The mechanisms underlying this anti-inflammatory action may be related to downregulation of NF-kappaB activity, involved in the generation of proinflammatory mediators.
Whittle
Brendan J R
BJ
Centre for Experimental Therapeutics, William Harvey Research Institute, Barts and the London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, UK. b.j.whittle@qmul.ac.uk
Varga
Csaba
C
Pósa
Anikó
A
Molnár
Andor
A
Collin
Marika
M
Thiemermann
Christoph
C
D000627:Aminophenols / Q000627:therapeutic use*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000188:drug therapy*; D003106:Colon / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D008301:Maleimides / Q000627:therapeutic use*; D009929:Organ Size / Q000187:drug effects; D009195:Peroxidase / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013830:Thiadiazoles / Q000627:therapeutic use*; D051996:Transcription Factor RelA / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
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; D004791:Enzyme Inhibitors; D008301:Maleimides; D013830:Thiadiazoles; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3