Protective effect of simvastatin in the cyclophosphamide-induced hemorrhagic cystitis in rats.
OBJECTIVE
Cyclophosphamide (CYP) is an antineoplastic agent used for the treatment of many neoplastic and inflammatory diseases. Hemorrhagic cystitis is a frequent side effect of CYP. Several studies show that simvastatin has important pleiotropic (anti-inflammatory and immunomodulatory) effects. The purpose of the study was to investigate the effect of simvastatin on bladder, ureter and kidney injury caused by CYP.


METHODS
Adult male Wistar rats were randomly divided into three groups. The CYP/SIM group received simvastatin microemulsion by gavage during 7 days (10 mg/kg body wt) before the administration of CYP and the CYP/SAL group rats received saline 0.9%. The control rats were not treated. After that, all rats were treated with a single dose of CYP 200 mg/kg body wt intraperitoneally. The rats were killed 24 h after CYP administration. Plasma cytokines (TNF-alpha, IL-1beta, IL-6) were measured by ELISA. Macro and light microscopic study was performed in the bladder, kidney and ureter.


RESULTS
In the bladders of CYP/SIMV treated rats edema of lamina propria with epithelial and sub-epithelial hemorrhage were lower than in CYP/SAL treated rats. The scores for macroscopic and microscopic evaluation of bladder and ureter were significantly lower in CYP/SIMV rats than in CYP/SAL rats. The kidney was not affected. The expression of TNF-alpha, IL-1beta and IL-6 was significatly lower in CF/SINV rats (164.8 + or - 22, 44.8 + or - 8 and 52.4 + or - 13) than in CF/SAL rats (378.5 + or - 66, 122.9 + or - 26 e 123.6 + or - 18), respectively.


CONCLUSIONS
The results of the current study suggest that simvastatin pretreatment attenuated CYP-induced urotelium inflammation and decreased the activities of cytokines.
Dantas
Anna Carolina Batista
AC
Center of Experimental Surgery, Department of Surgery, Federal University of Rio Grande do Norte (UFRN), Natal-RN, Brazil.
Batista-Júnior
Francisco Fábio de Araújo
FF
Macedo
Larissa Freitas
LF
Mendes
Mariana Noronha Castro
MN
Azevedo
Italo Medeiros
IM
Medeiros
Aldo Cunha
AC
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects*; D003520:Cyclophosphamide / Q000009:adverse effects*; D003556:Cystitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D006470:Hemorrhage / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000627:therapeutic use*; D014551:Urinary Tract / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D018906:Antineoplastic Agents, Alkylating; D016207:Cytokines; D003520:Cyclophosphamide; D019821:Simvastatin