Reduction of experimental colitis in the rat by inhibitors of glycogen synthase kinase‐3β

Abstract

1 The effects of the inhibitors of glycogen synthase kinase-3b (GSK-3b), 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. 2 Administration of the GSK-3b inhibitor TDZD-8 (0.1, 0.33 or 1.0 mg kg À1 , 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. 3 Likewise, following administration of the GSK-3b inhibitor SB 415286 (0.1, 0.33 or 1.0 mg kg À1 , s.c., b.i.d., for 3 days), the extent and degree of the TNBS-provoked colonic inflammation was reduced. 4 Administration of either TDZD-8 or SB 415286 reduced the fall in body weight following challenge with TNBS at each dose level studied. 5 The increase in myeloperoxidase activity, an index of neutrophil infiltration into the TNBSinduced inflamed colon, was significantly inhibited by both TDZD-8 and SB 415286 at each dose level. 6 The increase in the levels of the proinflammatory cytokine, TNF-a, in the inflamed colon was also significantly inhibited by either compound at the highest doses evaluated. 7 The elevated levels of the transcription factor NF-kB 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. 8 These findings demonstrate that two chemically distinct selective inhibitors of the activity of GSK3b 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-kB activity, involved in the generation of proinflammatory mediators.

PAR2-dependent activation of GSK3β regulates the survival of colon stem/progenitor cells

“…As a result, one can hypothesize that, in pathological situations associated with chronic activation of the PAR 2 -GSK3␤ pathway, this might result in impaired mucosal healing, and stem/ progenitor cell resistance to genotoxic insult, mutation accumulation, and acquisition of oncogenic properties. This would be particularly relevant in IBD that have been associated with PAR 2 and GSK3␤ (57,63). The PAR 2 /GSK3␤-induced stem cell survival and proliferation arrest, i.e., quiescence, could also participate in cancer stem cell resistance to therapy (32).…”

Pressure Overload Regulates Expression of Cytokines, γH2AX, and Growth Arrest- and DNA-Damage Inducible Protein 153 via Glycogen Synthase Kinase-3β in Ischemic-Reperfused Hearts

“…[27][28][29][30] With respect to myocardial IR injury, inhibition of GSK-3β reduces apoptosis and inflammatory indicators (ie, tumor necrosis factor-α and IL-6) in an in vivo model, likely reflecting both systemic and local contributions. 31 Importantly, isolated heart studies, using the Langendorff preparation, have established that the ischemic-reperfused heart mounts a robust inflammatory response.…”

Novel Anti-inflammatory Role for Glycogen Synthase Kinase-3β in the Inhibition of Tumor Necrosis Factor-α- and Interleukin-1β-induced Inflammatory Gene Expression

“…GSK-3␤ inhibitors have been shown to have beneficial effects in animal models of inflammation. Whittle et al (19) have shown that GSK-3␤ inhibitors TDZD-8 and SB 415286 can substantially reduce the systemic inflammation associated with endotoxic shock in vivo and the acute colitis provoked by trinitrobenzene sulfonic acid in the rat. Kinase inhibitors often show nonselective activity, and it is not clear whether the inhibition is entirely because of their effects on GSK-3␤.…”