Investigation of the therapeutic effect and possible mechanisms of fosaprepitant in the experimental cystitis model informed with cyclophospamide in mice

Inhibition of inflammatory process is a key therapeutic target for the treatment of interstitial cystitis (IC). Recent reports indicate neurokinin 1 receptor (NK1R) antagonists have important therapeutic roles in inflammatory-based diseases. Herein, we investigate the potential uroprotective effects of fosaprepitant (FOS), a NK1R antagonist, in cyclophosphamide (CP)-induced cystitis. The cystitis model was established multiple CP (80 mg/kg; i.p.) injection one day apart, and mice were treated with FOS (20 and 60 mg/kg/day; i.p.) or saline for seven consecutive days. Detrusor contractility, vesical vascular permeability, myeloperoxidase (MPO) activity and protein expression levels of the TLR4 pathway were evaluated in mice bladder. Carbachol and electric field stimulation-evoked contractions of detrusor strips were significantly increased in CP-treated mice, and this increase was significantly attenuated by FOS (60 mg/kg/day) treatment (p˂0.001, p˂0.05). Notably, vesical vascular permeability was markedly impaired in CP-induced cystitis, that was restored by FOS (60 mg/kg/day) treatment (p˂0.01). MPO activity was significantly increased in cystitis group whereas FOS (20 and 60 mg/kg/day) treatment remarkably suppressed this activity in bladder tissue (p˂0.001). Although TLR4 expression increased with cystitis, MyD88 and the ratio of p-NFκBser536/total NFκB did not change, FOS (20 and 60 mg/kg/day) treatment caused a dramatic decrease in TLR4 expression (p˂0.001), indicating thepotential antiinflammatory effect of FOS. In conclusion, FOS improved detrusor overactivity and inflammatory response by inhibiting MPO activity and TLR4 expression, resulting in functional and histological recovery in CP-induced cystitis.