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The effects of the inhibitors of glycogen synthase kinase‐3β (GSK‐3β), 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‐3β 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‐3β 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‐α, in the inflamed colon was also significantly inhibited by either compound at the highest doses evaluated. The elevated levels of the transcription factor NF‐κB 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‐3β 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‐κB activity, involved in the generation of proinflammatory mediators. British Journal of Pharmacology (2006) 147, 575–582. doi:10.1038/sj.bjp.0706509

Pharmacological GSK‐3 inhibitors are potential drugs for the treatment of neurodegenerative diseases, cancer and diabetes. We examined the antiproliferative effects of two GSK‐3 inhibitors, lithium and SB‐415286, on B65 neuroblastoma cell line. Treatment of B65 cells with either drug administered separately caused a decrease in cell proliferation that was associated with G2/M cell cycle arrest. Cell‐cycle proteins such as cyclins D, E, A, cdk4 and cdk2 were up‐regulated. Since lithium and SB‐415286‐induced G2/M arrest we studied changes in the expression of proteins involved in this phase, specifically cyclin B, cdc2 and the phosphorylated form of this protein (tyr15‐cdc2). Both drugs increased the expression of tyr15‐cdc2, thus inhibiting mitosis. On the other hand, SB‐415286 increased the expression of SIRT2, involved in the regulation of proliferation. Moreover, cell‐cycle arrest mediated by SB‐415286 was accompanied by apoptosis that was not prevented by 100 μM of zVAD‐fmk (benzyloxycarbonyl‐Val‐Ala‐Asp‐fluoromethylketone), a pan‐caspase inhibitor. Likewise, GSK‐3 inhibitors did not affect the mitochondrial release of apoptosis inducing factor (AIF). We conclude that inhibitors of GSK‐3 induced cell‐cycle arrest, mediated by the phosphorylation of cdc2 and, in the case of SB‐415286, SIRT2 expression, which induced apoptosis in a caspase‐independent manner.