Investigation of the uroprotective effect and possible mechanisms of sitagliptin in a cyclophosphamide-induced experimental cystitis model in mice

Suppression of inflammatory responses is considered one of the primary therapeutic targets in the treatment of interstitial cystitis (IC). Previous studies have demonstrated that sitagliptin possesses significant potential in the treatment of inflammation-related diseases. In this study, we investigated the uroprotective effect of sitagliptin (Sita) in cyclophosphamide (CP)-induced acute experimental cystitis and its possible association with the TLR-4/NFκB signaling pathway, which we hypothesized may play an important role in this effect. The acute cystitis model was established by a single CP injection (300 mg/kg) following 5 days of sitagliptin treatment. Mice were treated with sitagliptin (20 and 100 mg/kg/day, i.p.) or physiological saline for five consecutive days. Detrusor contractility, bladder edema, glutathione (GSH), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) levels, as well as the expression levels of total NFκB, phosphorylated NFκB (p-NFκB), and TLR4 proteins of the NFκB/TLR4 signaling pathway, were evaluated in bladder tissue. KCl-induced contractile responses of detrusor strips showed no significant differences between groups. CP significantly reduced carbachol (CCh)-induced detrusor contractions, decreased bladder GSH levels, and increased IL-1β and TNF-α levels. CP also markedly enhanced TLR4 protein expression and NFκB phosphorylation. Mesna treatment prevented the CP-induced reduction in detrusor contractile responses and GSH levels, suppressed inflammatory responses, and inhibited CP-induced NFκB phosphorylation, but did not significantly alter TLR4 levels. Treatment with sitagliptin at 100 mg/kg prevented the CP-induced reduction in CCh-induced maximal contractile response and the increases in bladder IL-1β levels and NFκB phosphorylation, while it had no effect on TNF-α or TLR4 expression levels. At a dose of 20 mg/kg, Sita had no effect on detrusor contraction responses, inflammatory markers (IL-1β, TNF-α), and NFkB and TLR4 levels. Our results provide evidence that at a dose of 100 mg/kg, Sita may have a therapeutic effect in CP-induced acute cystitis by regulating detrusor contraction and inflammatory responses in the bladder.