Trimetazidine attenuates cyclophoshamide-induced cystitis in mice by inhibiting TLR4/NFκB signaling pathway


Engin S. , Barut E. N. , Kaya Yaşar Y. , Kerimoğlu G. , Duman M. , Sezen F. S.

3rd International Gazi Pharma Symposium Series, Ankara, Turkey, 8 September - 10 October 2021, pp.68-69

  • Publication Type: Conference Paper / Summary Text
  • City: Ankara
  • Country: Turkey
  • Page Numbers: pp.68-69

Abstract

Cyclophosphamide (CP)-induced cystitis is a challenging clinical problem involving inflammation and dysfunction of bladder (1). Trimetazidine (TMZ) is an anti-anginal drug with anti-oxidant and anti-inflammatory properties (2). However, its effect on CP-induced cystitis is unknown. We aimed to investigate the potential protective effects of TMZ in CP-induced cystitis via inhibiting TLR4/NFκB pathway and its effect on the anti-tumor activity of CP. Cystitis was induced by a single injection of CP (300 mg/kg; i.p) in mice and  TMZ was administered (10 and 20 mg/kg/day; i.p.) for 5 consecutive days before CP. 24 hours after cystitis induction, the bladders were removed for  histopathological evaluation, functional contractility studies, biochemical analysis and western blotting. Effect of TMZ on the anti-tumor activity of CP  was evalauted  in  MDA-MB-231 cells with MTT assay (3,4). CP caused severe cystitis confirmed by histological alterations, which was partially ameliorated by TMZ. CP-induced cystitis caused a signifcant decrease in the carbachol-evoked contractions of bladder strips and TMZ (20 mg/kg) pretreatment restored the contractile response. SOD activity and GSH content –biomarkers of antioxidant status- were significantly increased and, TNF-α and IL-1β levels –proinflammatory cytokines- were markedly decreased in the bladders of  TMZ-pretreated mice compared to CP. TMZ reduced the CP-induced increase in TLR4 expression and NFκB phosphorylation in the bladders. TMZ alone and CP co-treatment decreased the cell viability. Our study provides the first evidence that TMZ attenuates CP-induced urotoxicity due to its anti-oxidant and anti-inflammatory effects possibly via downregulating TLR4/NFκB signaling while not inerfering with the anti-tumor activity of CP.