RHO KINASE INHIBITION AMELIORATESCYCLOPHOSPHAMIDE- INDUCED CYSTITIS IN RATS
A. A. WROBEL 1, E.RECHBERGER 2, T. RECHBERGER3, K. A.SKORUPSKA 4, P. MIOTLA 5;
1Med.Univ., Lublin, Poland, 2Med. Univ. of lublin, lublin,Poland, 3II Dept. of Gynecology Med. Univ., Lublin,Poland, 42nd Dept. of Gynecology UM in Lublin, Lublin,Poland, 52nd Dept. of Gynecology, Med. Univ., Lublin,Poland.
Introduction: Hemorrhagiccystitis (HC) is a life-threating condition defined by symptoms thatinclude hematuria and bladder detrusor overactivity. HC occurs in 10to 40% of patients receiving high-dose cyclophosphamide (CYP). HCinduced by CYP may require a variety of procedures and can be fatal.Hence, there is a need for novel treating agents. Evidence suggeststhat Rho kinase (ROCK) is an interesting target for the treatment ofbladder overactivity. Moreover, as ROCK inhibitors were found to beactive in several animals models of OAB, direct inhibition of ROCKhas been proposed as a novel strategy for the treatment of OAB.CYP-induced HC is an inflammation, initiated by the contact of CYPliver metabolite, acrolein, with urothelium, in which proinflammatorycytokines (TNF-α and Il-1β) and transcription factors (NF-κB)participate. One of the mechanisms of inflammatory events is theeffect on NF-κB. ROCK can activate NF-κB, therefore, its inhibitionseems to be a possible therapeutic strategy for the treatment ofCYP-induced HC.
Objective: The aim of this study was totest whether GSK 269962 would rescue cystometric and inflammatorychanges in a model of cystitis induced by CYP injection.
Methods:GSK 269962 was administered intravenously (i.v.) at a daily dose of30 mg/kg. CYP was administered i.p. at a single dose of 200 mg/kg.The control rats received volume-matched saline i.p. The ratsreceived GSK 269962 or vehicle for 7 days. On day 7, the animalsreceived CYP or a corresponding volume of saline. On day 8 thesurgical procedures were performed. On day 9 cystometric studies,bladder edema and urothelium thickness measurements were performed(1).
Results: One-way ANOVA demonstrated significantchanges in cystometric parameters: BP, MVP , VV, PVR, VT, ICI, BCD,RT, BC, DOI, ANVC, FNVC, VTNVC (Fig. 1A,B,C) between the examinedgroups. The following parameters were significantly increased in CYPinjected rats: BP, TP, BCD, RT, DOI, ANVC, FNVC, whereas: MVP, VV,PVR, VT, ICI, BC, VTNVC parameters were significantly decreased inthose rats. VE parameter did not differ significantly between theexamined groups. One-way ANOVA demonstrated significant changes in EBextravasation into bladder tissue (Fig. 2A) and urothelium thickness(Fig. 2B).
Conclusions: Administration of GSK 269962normalized CYP injection-induced changes in the above mentionedparameters and did not significantly affect their values in controlanimals.CYP injection increased EB extravasation and decreasedurothelium thickness whereas administration of GSK 269962 attenuatedthese changes in CYP-injected rats and did not affect their values incontrol animals.
References: All procedures were conductedin accordance with the 2010/63/EU and were approved by the LocalEthics Committee.