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Oral Poster 13
INTRAVESICAL TREATMENT WITH MEFLOQUINE, A PANNEXIN 1 CHANNEL BLOCKER, IMPROVES BLADDER FUNCTION IN MICE WITH CYCLOPHOSPHAMIDE-INDUCED HEMORRHAGIC CYSTITIS.

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Introduction:

Perception of bladder distension is crucial for coordination and initiation of the micturition reflex. It has been proposed that ATP released from urothelial cells in response to bladder distension may communicate bladder fullness by stimulating afferent nerve fibers within the urothelium and in the suburothelial nerve plexus. Several receptors and channels have been shown to participate in mechanisms of urothelial ATP release and we have recently demonstrated that Pannexin 1 (Panx1) is one of these channels.

Objectives:

The goal of this study was to perform a pre-clinical evaluation of mefloquine (MFQ) as a novel drug for intravesical treatment of chemically-induced hemorrhagic cystitis (HC).

Material and Method:

We used the cyclophosphamide (CYP)-induced model of HC and 10 weeks old male wild-type mice.

Animals were divided in two groups: CYP+Saline and CYP+MFQ. Each mouse received a single IP injection of 300 mg/kg CYP and continuous saline infusion cystometry (1.5 mL/hr) was performed 30 min after injection to obtain a baseline for CYP-induced changes in bladder function. Animals were then allowed 30 min rest from continuous saline infusion, and cystometry restarted with MFQ (300nM; CYP-MFQ group) or without MFQ (CYP-Saline group) infusion (Figure 1). Representative cystometric recordings for both groups before and after bladder rest are shown in Figure 2.

Cystometric parameters measured were: bladder capacity (volume of infused saline at micturition); basal pressure (lowest average intraluminal pressure recorded during cystometry); threshold pressure (bladder pressure immediately before micturition); micturition pressure (peak intraluminal pressure during micturition); micturition volume (volume of urine discharged during micturition); bladder compliance (bladder capacity divided by threshold minus basal pressure).

Parameters measured from each group after the resting period were compared with baseline CYP values within the same group. Cystometric data are represented as mean±SEM, N=number of micturition cycles analyzed. Significance determined at p<0.05, using t-test.

Results:

Average body weight (CYP-Saline, 23.8±0.5g, n=3; CYP-MFQ, 23.1±0.2g, n=4), bladder weight (CYP-Saline, 40.6±1.5mg; CYP-MFQ, 39.3±5.7mg), and bladder-body weight ratio (CYP-Saline, 1.71±0.1; CYP-MFQ, 1.70±0.2) were not significantly different between groups (Figure 3).
Cystometric analysis indicated that bladder function in CYP-treated mice improved significantly after intravesical treatment with MFQ, as indicated by the increase in bladder capacity, decrease in bladder pressure and in inter-micturition pressure values relative to values from the same animal before treatment (Table 1, Figure 4). 

Conclusion:

Intravesical treatment with MFQ results in rapid amelioration of irritative voiding symptoms in mice with CYP-induced HC. This finding indicates that Panx1 blockade may provide a novel therapeutic approach to manage HC in patients undergoing chemotherapy.


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