Trimetazidine attenuates cyclophosphamide-induced cystitis by inhibiting TLR4-mediated NF Kappa B signaling in mice

Engin S., Barut E. N., Yaşar Y. K., Soysal A. Ç., Arıcı T., Kerimoğlu G., ...More

LIFE SCIENCES, vol.301, 2022 (SCI-Expanded, Scopus) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 301
  • Publication Date: 2022
  • Doi Number: 10.1016/j.lfs.2022.120590
  • Journal Name: LIFE SCIENCES
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chimica, EMBASE, MEDLINE, Veterinary Science Database
  • Keywords: Bladder dysfunction, Cyclophosphamide, Cystitis, Inflammation, MTT assay, Toll-like receptors, IMPROVES BLADDER FUNCTION, ISCHEMIA/REPERFUSION INJURY, ACTIVATION, DYSFUNCTION, MECHANISMS, PROTECTION, RECEPTORS, TOXICITY, MODELS, AGENTS
  • Karadeniz Technical University Affiliated: Yes

Abstract

Aim: 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/ NF Kappa B signaling.Main methods: 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 (2mercaptoethane 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.Key findings: CP-induced severe cystitis was confirmed by histological disturbances and the decrease in carbacholevoked contractions of detrusor strips, which was partially improved by TMZ (20 mg/kg/day). SOD activity and GSH content were decreased whereas TNF-alpha and IL-1 beta 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-NF Kappa B in bladder tissues. TMZ alone decreased the cell viability and TMZ also enhanced the cytotoxicity of CP.Significance: 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 NF Kappa B signaling while augmenting the cytotoxicity of CP.