Sesquiterpene Lactone Parthenolide Ameliorates Bladder Inflammation and Bladder Overactivity in Cyclophosphamide Induced Rat Cystitis Model by Inhibiting Nuclear Factor-κB Phosphorylation

Purpose: Cyclophosphamide (Sigma (R)) is associated with urological complications, including irritative voiding symptoms and hemorrhagic cystitis. Evidence suggests that tumor necrosis factor-alpha (R & D Systems (R)), interleukin-1 beta and cyclooxygenase-2 are directly involved in the pathogenesis of induced cystitis and these molecules depend on transcription factor NF-kappa B for maximal secretion. Additionally, sesquiterpene lactone parthenolide has been shown to be a potent nuclear factor-kappa B inhibitor. We hypothesized that enhanced nuclear factor-kappa B activity contributes to cyclophosphamide induced cystitis and, therefore, it may be an attractive target for preventing cyclophosphamide cystitis. We determined whether parthenolide could be used as a preventive agent for hemorrhagic cystitis and bladder overactivity. Moreover, we determined the molecular mechanisms of parthenolide on the inhibitory action of nuclear factor-kappa B in inflammatory human benign urothelial cells. Materials and Methods: Rats were pretreated with parthenolide or vehicle solution and administered cyclophosphamide. Histological analysis and cystometry were performed 24 hours after cyclophosphamide administration. Human urothelial cells were pretreated with parthenolide and stimulated with tumor necrosis factor-alpha. Western blotting and immunofluorescence were performed to determine activation of the cyclooxygenase-2 and nuclear factor-kappa B pathway. Results: Parthenolide pretreatment inhibited bladder inflammation as well as bladder overactivity and it was also associated with nuclear factor-kappa B activation in the bladder. Parthenolide dose dependently suppressed tumor necrosis factor-a induced cyclooxygenase-2 expression and prevented nuclear factor-kappa B phosphorylation as well as nuclear factor-kappa B nuclear translocation and IKB alpha phosphorylation/degradation. Conclusions: Nuclear factor-kappa B may have a crucial role in the pathogenesis of cyclophosphamide induced cystitis models. Parthenolide ameliorates bladder inflammation and bladder overactivity, and it might be a promising agent for preventing cyclophosphamide induced complications.