Sesquiterpene lactone parthenolide ameliorates bladder inflammation and bladder overactivity in cyclophosphamide induced rat cystitis model by inhibiting nuclear factor-kappaB phosphorylation.
OBJECTIVE
Cyclophosphamide (Sigma) is associated with urological complications, including irritative voiding symptoms and hemorrhagic cystitis. Evidence suggests that tumor necrosis factor-alpha (R&D Systems), interleukin-1beta and cyclooxygenase-2 are directly involved in the pathogenesis of cyclophosphamide induced cystitis and these molecules depend on transcription factor NF-kappaB for maximal secretion. Additionally, sesquiterpene lactone parthenolide has been shown to be a potent nuclear factor-kappaB inhibitor. We hypothesized that enhanced nuclear factor-kappaB 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-kappaB in inflammatory human benign urothelial cells.


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-kappaB pathway.


RESULTS
Parthenolide pretreatment inhibited bladder inflammation as well as bladder overactivity and it was also associated with nuclear factor-kappaB activation in the bladder. Parthenolide dose dependently suppressed tumor necrosis factor-alpha induced cyclooxygenase-2 expression and prevented nuclear factor-kappaB phosphorylation as well as nuclear factor-kappaB nuclear translocation and IkappaBalpha phosphorylation/degradation.


CONCLUSIONS
Nuclear factor-kappaB 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.
Kiuchi
Hiroshi
H
Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan.
Takao
Tetsuya
T
Yamamoto
Keisuke
K
Nakayama
Jiro
J
Miyagawa
Yasushi
Y
Tsujimura
Akira
A
Nonomura
Norio
N
Okuyama
Akihiko
A
D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D003520:Cyclophosphamide / Q000009:adverse effects* / Q000494:pharmacology; D003556:Cystitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D012717:Sesquiterpenes / Q000378:metabolism / Q000494:pharmacology*; D053201:Urinary Bladder, Overactive / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*
D016328:NF-kappa B; D012717:Sesquiterpenes; C002669:parthenolide; D003520:Cyclophosphamide