Novel complementary coloprotective effects of metformin and MCC950 by modulating HSP90/NLRP3 interaction and inducing...

Ulcerative colitis (UC) is a chronic and relapsing inflammatory disorder, which has an increased incidence worldwide. The NLRP3 inflammasome has recently been assigned as a promising target for several inflammatory diseases including bowel inflammation. We aimed to investigate the potential complementary effects of combined therapy of metformin and MCC950 in dextran sodium sulfate (DSS)-induced colitis in rats. Metformin/MCC950 mitigated colon shortening, disease activity index (DAI), and macroscopic damage index (MDI). It also improved the colon histology picture and reduced the inflammation score. In addition, metformin/MCC950 augmented the antioxidant defense machinery and attenuated the myeloperoxidase (MPO) activity. Moreover, the levels of the pro-inflammatory mediators tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) were reduced. This pharmacological activity might be attributed to interrupting the priming signal of the NLRP3 inflammasome activation through inactivating Toll-like receptor 4 (TLR4)/nuclear transcription factor kappa-B (NF-κB) signalling (effect of metformin) as well as interrupting the activation signal through potent inhibition of NLRP3 expression and caspase-1 (effect of MCC950). As a result, significant inhibition of the production of the bioactive IL-1β and IL-18 occurred, and hence the pyroptosis process was inhibited. Moreover, the metformin/MCC950 leads to the induction of autophagy by AMP-activated protein kinase (AMPK)-dependent mechanisms leading to the accumulation of Beclin-1 and a substantial decline in the levels of p62 SQSTM1 (effect of metformin). The observed impeding effect on HSP90 along with inducing autophagy (effect of metformin) suggests that NLRP3 is prone to autophagic degradation. In conclusion, we reveal that the combination of metformin with MCC950 has a protective role in DSS-induced colitis and might become a candidate in a promising approach for the future treatment of human UC.