Trimetazidine attenuates cyclophosphamide-induced cystitis by inhibiting TLR4-mediated NFκB signaling in mice

• DOI: 10.1016/j.lfs.2022.120590
• Publication Date: 2022-04-30T14:53:21Z
• Authors: Seçkin Engin; Elif Nur Barut; Yeşim Kaya Yaşar; Aysun Çelik Soysal; Tuğba Arıcı; Gökçen Kerimoğlu; Mine Kadıoğlu; Sena F. Sezen
• Keywords: Inflammation; Mice, Inbred BALB C; 0303 health sciences; NF-kappa B; Trimetazidine; Antioxidants; 3. Good health; Toll-Like Receptor 4; Mice; 03 medical and health sciences; Cystitis; Animals; Cyclophosphamide; Mesna

Cyclophosphamide (CP)-induced cystitis is a challenging clinical problem involving inflammation and dysfunction of bladder. Trimetazidine (TMZ) is an anti-anginal drug with anti-oxidant and anti-inflammatory properties. We aimed to investigate the protective effects of TMZ in CP-induced cystitis via inhibiting TLR4/NFκB signaling.Balb/c mice were administrated TMZ (10 or 20 mg/kg/day) intraperitoneally (i.p.) for 5 consecutive days before CP. On day 6, cystitis was induced by a single dose of CP (300 mg/kg, i.p.). Mesna (2-mercaptoethane sulfonate sodium; 30 mg/kg, i.p.) was administered 20 min before and at 4 and 8 h after the CP injection. After 24 h of cystitis induction, the bladders were removed for histopathological evaluation, contractility studies, biochemical analysis and western blotting. MTT assay was performed in a cancer cell line (MDA-MB-231) to evaluate the effect of TMZ on the cytotoxicity of CP.CP-induced severe cystitis was confirmed by histological disturbances and the decrease in carbachol-evoked contractions of detrusor strips, which was partially improved by TMZ (20 mg/kg/day). SOD activity and GSH content were decreased whereas TNF-α and IL-1β levels were increased in the bladders of CP-treated mice, which were restored by TMZ or mesna. TMZ reduced the CP-induced increase in the protein expressions of caspase-3, TLR4 and phosphorylated-NFκB in bladder tissues. TMZ alone decreased the cell viability and TMZ also enhanced the cytotoxicity of CP.Our study provides the first preclinical evidence that TMZ attenuates CP-induced urotoxicity by enhancing anti-oxidant capacity and suppressing inflammation possibly via downregulating TLR4-mediated NFκB signaling while augmenting the cytotoxicity of CP.