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The endocannabinoid system is a signaling system involved in a wide range of biological effects. Literature strongly suggests the endocannabinoid system role in the pathogenesis of cancer and that its pharmacological activation produces therapeutic benefits. Last research promotes the endocannabinoid system modulation by inhibition of endocannabinoids hydrolytic enzymes instead of direct activation of endocannabinoid receptors to avoid detrimental effects on cognition and motor control. Here we report the identification of N-acylethanolamine-hydrolyzing acid amidase (NAAA) inhibitors able to reduce cell proliferation and migration and cause cell death on different bladder cancer cell lines. These molecules were designed, synthesized and characterized and active compounds were selected by a fluorescence high-throughput screening method set-up on human recombinant NAAA that also allows to characterize the mechanism of inhibition. Together our results suggest an important role for NAAA in cell migration and in inducing tumor cell death promoting this enzyme as pharmacological target against bladder cancer., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Information on autonomic neurapraxia in female urogenital surgery is scarce, and a model to study it is not available., Objective: To develop a model to study the impact of autonomic neurapraxia on bladder function in female rats, as well as to assess the effects of corticosteroid therapy on the recovery of bladder function in this model., Design, Setting, and Participants: Female Sprague-Dawley rats were subjected to bilateral pelvic nerve crush (PNC) and perioperatively treated with betamethasone or vehicle. Bladder function and morphology of bladder tissue were evaluated and compared with sham-operated rats., Outcome Measurements and Statistical Analysis: Western blot, immunohistochemistry, organ bath experiments, and cystometry., Results and Limitations: Sham-operated rats exhibited regular micturitions without nonvoiding contractions (NVCs). Crush of all nerve branches of the pelvic plexus or PNC resulted in overflow incontinence and/or NVCs. Betamethasone treatment improved recovery of regular micturitions (87.5% compared with 27% for vehicle; p<0.05), reduced lowest bladder pressure (8 ± 2 cm H(2)O compared with 21 ± 5 cm H(2)O for vehicle; p<0.05), and reduced the amplitude of NVCs but had no effect on NVC frequency in PNC rats. Compared with vehicle, betamethasone-treated PNC rats had less CD68 (a macrophage marker) in the pelvic plexus and bladder tissue. Isolated bladder from betamethasone-treated PNC rats exhibited better nerve-induced contractions, contained more cholinergic and sensory nerves, and expressed lower amounts of collagen III than bladder tissue from vehicle-treated rats., Conclusions: PNC causes autonomic neurapraxia and functional and morphologic changes of isolated bladder tissue that can be recorded as bladder dysfunction during awake cystometry in female rats. Perioperative systemic betamethasone treatment reduced macrophage contents of the pelvic plexus and bladder, partially counteracted changes in the bladder tissue, and had protective effects on micturition function., (Copyright © 2012. Published by Elsevier B.V.)

Background: The schedule for intravesical chemotherapy administration has not been definitively established in patients with low-grade recurrent non-muscle-invasive bladder cancer (NMIBC)., Objective: To assess both the feasibility and the efficacy of a short-term intensive schedule of neoadjuvant intravesical chemotherapy in patients with recurrent NMIBC., Design, Setting, and Participants: A randomised phase 2 clinical study included 54 patients with recurrent NMIBC who were submitted to neoadjuvant chemotherapy intravesical instillations according to two different timing schedules. The study was performed at a tertiary care referral centre., Intervention: Intravesical mitomycin C (MMC) 40 mg/40 ml was administered according to a schedule of either one instillation per week for 6 wk (group 1) or three instillations per week for 2 wk (group 2) prior to transurethral resection (TUR)., Outcome Measurements and Statistical Analysis: Local and systemic toxicity were investigated using the US National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 questionnaire at each instillation and the SF-36 questionnaire at randomisation and before TUR. A video-recorded cystoscopy and TUR were performed within 14 d after treatment completion., Results and Limitations: Groups 1 and 2 each were assigned 27 cases. Two patients (7.4%) in group 2 could not complete the scheduled treatment because of severe lower urinary tract symptoms. No statistically significant difference in SF-36 domain score was documented pre- and post-treatment between groups. Likewise, no statistically significant difference in treatment-related toxicity according to the CTCAE v.4 questionnaire was registered. Twelve patients (44.4%) in group 1 and 19 patients (70.4%) in group 2 (p=0.054) had complete tumour response. The small number of patients included represents the main limitation of the study., Conclusions: The intensive short-term schedule of neoadjuvant chemotherapy is safe and without additional toxicity compared with the weekly regimen. The increased ablative effect may be explained by the improved adherence of the scheduled timing to the duplication rate of tumour cells., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Cannabinoid receptor (CB)-mediated functions may be involved in the regulation of bladder function, but information on endocannabinoid signals during micturition is scarce., Objective: Investigate the expression of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) in human, rat, and mouse bladders and study the effects of inhibition of FAAH during urodynamics in awake rats., Design, Setting, and Participants: Bladder tissue from humans, mice, and rats was used for measurements. Female Sprague-Dawley rats were administered the FAAH inhibitor oleoyl ethyl amide (OEtA) or vehicle intravenously (IV) or intravesically (IVES) with or without rimonabant (CB1 antagonist) or SR144528 (CB2 antagonist)., Measurements: Real-time transcriptase-polymerase chain reaction, Western blot, immunohistochemistry, and cystometry in awake rats., Results and Limitations: Messenger RNA and protein for FAAH was expressed in the mucosa of human, mouse, and rat urinary bladders. Immunoreactivities for FAAH and CB2 were codistributed in rat and human urothelium. IV OEtA (0.3mg/kg) to rats increased intercontraction intervals (ICIs), micturition volume (MV), bladder capacity (BC), and threshold pressure (TP) by 17±1%, 16±1%, 17±1%, and 19±5%, respectively (all p<0.05 vs baseline). IVES OEtA (1 and 10mg/l) in rats dose-dependently increased (p<0.05 vs baseline) ICI (19±2% and 35±5%), MV (15±3% and 32±4%), BC (16±2% and 34±4%), and TP (15±1%, 21±3%). SR144528 (IVES 5mg/l) abolished all effects of OEtA, whereas rimonabant only counteracted effects of OEtA on TP., Conclusions: Bladder mucosa of all species expressed FAAH. Rat and human urothelium coexpressed FAAH and CB2. The FAAH inhibitor OEtA altered urodynamic parameters that reflect sensory functions of micturition in rats. Suggesting a role for the endocannabinoid system in bladder mechanoafferent functions of rats, effects of IVES OEtA were abolished by an IVES CB2 antagonist and partly counteracted by an IVES CB1 antagonist., (Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.)