Hyaluronan nanoplatelets exert an intrinsic anti-inflammatory activity in a rat model of bladder painful syndrome/interstitial cystitis.

Glycosaminoglycan (GAG) replenishment therapy consists of the instillation of GAG solutions directly in the bladder to alleviate Bladder Painful Syndrome/Interstitial Cystitis (BPS/IC). However, several issues were reported with this strategy because the GAG solutions are rapidly eliminated from the bladder by spontaneous voiding, and GAG have low bioadhesive behaviors. Herein, GAG nanomaterials with typical flattened morphology were obtained by a self-assembly process. The formation mechanism of those nanomaterials, denoted as nanoplatelets, involves the interaction of α-cyclodextrin cavity and alkyl chains covalently grafted on the GAG. Three GAG were used in this investigation, hyaluronan (HA), chondroitin sulfate (CS), and heparin (HEP). HA NP showed the best anti-inflammatory activity in an LPS-induced in vitro inflammation model of macrophages. They also exhibited the best therapeutic efficacy in a BPS/IC rat inflammation model. Histological examinations of the bladders revealed that HA NP significantly reduced bladder inflammation and regenerated the bladder mucosa. This investigation could open new perspectives to alleviate BPS/IC through GAG replenishment therapy.

Early Detrusor Application of Botulinum Toxin A Results in Reduced Bladder Hypertrophy and Fibrosis after Spinal Cord Injury in a Rodent Model.

Following spinal cord injury (SCI), pathological reflexes develop that result in altered bladder function and sphincter dis-coordination, with accompanying changes in the detrusor. Bladder chemodenervation is known to ablate the pathological reflexes, but the resultant effects on the bladder tissue are poorly defined. In a rodent model of contusion SCI, we examined the effect of early bladder chemodenervation with botulinum toxin A (BoNT-A) on bladder histopathology and collagen deposition. Adult female Long Evans rats were given a severe contusion SCI at spinal level T9. The SCI rats immediately underwent open laparotomy and received detrusor injections of either BoNT-A (10 U/animal) or saline. At eight weeks post injury, the bladders were collected, weighed, and examined histologically. BoNT-A injected bladders of SCI rats (SCI + BoNT-A) weighed significantly less than saline injected bladders of SCI rats (SCI + saline) (241 ± 25 mg vs. 183 ± 42 mg; p < 0.05). Histological analyses showed that SCI resulted in significantly thicker bladder walls due to detrusor hypertrophy and fibrosis compared to bladders from uninjured animals (339 ± 89.0 µm vs. 193 ± 47.9 µm; p < 0.0001). SCI + BoNT-A animals had significantly thinner bladder walls compared to SCI + saline animals (202 ± 55.4 µm vs. 339 ± 89.0 µm; p < 0.0001). SCI + BoNT-A animals had collagen organization in the bladder walls similar to that of uninjured animals. Detrusor chemodenervation soon after SCI appears to preserve bladder tissue integrity by reducing the development of detrusor fibrosis and hypertrophy associated with SCI.

Long-term conservative management of symptomatic bladder endometriosis: A case series of 17 patients.

OBJECTIVES: This study aimed to evaluate the course of long-term conservative management of bladder endometriosis (BE). MATERIALS AND METHODS: We retrospectively reviewed 17 cases of BE conservatively managed without surgery in our facility. The following factors were analyzed: age, medical history, lesion size, symptoms, hormonal treatment, and follow-up outcomes. RESULTS: In this study, 15 patients received hormonal therapy and 2 did not. Oral contraceptive (OC), dienogest (DNG), and gonadotropin-releasing hormone agonist (GnRHa) were administered as the first regimen in 7, 5, and 3 patients, respectively. Of the 7 patients, OC administration was effective in alleviating urinary symptoms in all but 2 patients. Of 3 patients who received GnRHa, 2 switched to OC and then DNG, and 1 patient discontinued the treatment because of adverse effects. Of 5 patients who received DNG, all experienced symptom relief. DNG, OC, and GnRHa administration were effective and tolerable in 9 of 10 patients (90.0%), in 5 of 9 patients (55.6%), and in 2 of 3 patients (66.7%), respectively. In particular, 3 patients completed DNG treatment until menopause. The size of the BE lesion significantly decreased after 3 months of DNG administration, and the reduction effect was maintained until 48 months thereafter. CONCLUSION: This study proposed that hormonal therapy for BE is an effective option for those who are not planning to conceive or to undergo surgery. Specifically, DNG may be suitable for patients refusing surgery, considering the effectiveness and tolerance for long-term use.

The TRPM8 channel as a potential therapeutic target for bladder hypersensitive disorders.

In the lower urinary tract, transient receptor potential (TRP) channels are primarily involved in physiological function, especially in cellular sensors responding to chemical and physical stimuli. Among TRP channels, TRP melastatin 8 (TRPM8) channels, responding to cold temperature and/or chemical agents, such as menthol or icilin, are mainly expressed in the nerve endings of the primary afferent neurons and in the cell bodies of dorsal root ganglia innervating the urinary bladder (via Aδ- and C-fibers); this suggests that TRPM8 channels primarily contribute to bladder sensory (afferent) function. Storage symptoms of overactive bladder, benign prostatic hyperplasia, and interstitial cystitis are commonly related to sensory function (bladder hypersensitivity); thus, TRPM8 channels may also contribute to the pathophysiology of bladder hypersensitivity. Indeed, it has been reported in a pharmacological investigation using rodents that TRPM8 channels contribute to the pathophysiological bladder afferent hypersensitivity of mechanosensitive C-fibers. Similar findings have also been reported in humans. Therefore, a TRPM8 antagonist would be a promising therapeutic target for bladder hypersensitive disorders, including urinary urgency or nociceptive pain. In this review article, the functional role of the TRPM8 channel in the lower urinary tract and the potential of its antagonist for the treatment of bladder disorders was described.

Inhibition of CXCR4 in Spinal Cord and DRG with AMD3100 Attenuates Colon-Bladder Cross-Organ Sensitization.

BACKGROUND: Cross-sensitization of pelvic organs is one theory for why symptoms of gut sickness and interstitial cystitis/bladder pain syndrome overlap. Experimental colitis has been shown to trigger bladder hyperactivity and hyperalgesia in rats. The chemokine receptor CXCR4 plays a key role in bladder function and central sensitization. We aim to study the role of CXCR4 and its inhibitor AMD3100 in colon-bladder cross-organ sensitization. METHODS: The colitis model was established by rectal infusion of trinitrobenzene sulfonic acid. Western blot and immunofluorescence were used to assess the expression and distribution of CXCR4. Intrathecal injection of AMD3100 (a CXCR4 inhibitor) and PD98059 (an ERK inhibitor) were used to inhibit CXCR4 and downstream extracellular signal-regulated kinase (ERK) in the spinal cord and dorsal root ganglion (DRG). Intravesical perfusion of resiniferatoxin was performed to measure the pain behavior counts of rats, and continuous cystometry was performed to evaluate bladder voiding function. RESULTS: Compared to the control group, CXCR4 was expressed more in bladder mucosa and colon mucosa, L6-S1 dorsal root ganglion (DRG), and the corresponding segment of the spinal dorsal horn (SDH) in rats with colitis. Moreover, intrathecal injection of the AMD3100 suppressed bladder overactivity, bladder hyperalgesia, and mastocytosis symptoms caused by colitis. Furthermore, AMD3100 effectively inhibited ERK activation in the spinal cord induced by experimental colitis. Finally, treatment with PD98059 alleviated bladder overactivity and hyperalgesia caused by colitis. CONCLUSION: Increased CXCR4 in the DRG and SDH contributes to colon inflammation-induced bladder overactivity and hyperalgesia partly via the phosphorylation of spinal ERK. Treatment targeting the CXCR4/ERK pathway might provide a potential new approach for the comorbidity between the digestive system and the urinary system.

Impact of perioperative use of GnRH agonist or dienogest on ovarian reserve after cystectomy for endometriomas: a randomized controlled trial.

BACKGROUND: Ovarian endometrioma is a common gynecological disease that is often treated with surgery or hormonal treatment. Ovarian cystectomy, a surgical procedure for ovarian endometrioma, can result in impaired ovarian reserve. METHODS: We conducted a randomized controlled trial to evaluate the efficacy of hormonal treatment [gonadotropin-releasing hormone agonist (GnRHa) or dienogest (DNG)] for preserving ovarian reserve after cystectomy for ovarian endometrioma. The primary endpoint was the level of serum Anti-Müllerian hormone (AMH) as a marker of ovarian reserve. RESULTS: Before and after laparoscopic surgery, 22 patients in the GnRHa group and 27 patients in the DNG group were administered hormonal treatment for a total of 4 months. After 1-year follow-up, >60% of the patients in the DNG group retained over 70% of their pretreatment AMH levels, whereas no patient in the GnRHa group retained their AMH levels after cystectomy (P < 0.01). Interleukin-6 (IL-6) is a key cytokine involved in inflammation. Compared with the GnRHa group, patients in the DNG group had lower IL-6 levels at the end of treatment. CONCLUSIONS: Our data revealed that DNG is more effective than GnRHa in preserving ovarian reserve after cystectomy of ovarian endometrioma. This is achieved through the reduction of the inflammatory response during the perioperative period and other endometriosis-related inflammatory reactions. TRIAL REGISTRATION: The registration number of this trial is UMIN-CTR, UMIN000018569, registered 6 August 2015, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021492 , and Japan Registry of Clinical Trials, jRCTs041180140, registered 29 March 2019, https://jrct.niph.go.jp/en-latest-detail/jRCTs041180140 . This randomized controlled trial was conducted in accordance with the CONSORT guidelines.

Prostanoid TP receptor stimulation enhances contractile activities in guinea pig urinary bladder smooth muscle through activation of Ca2+ entry channels: Potential targets in the treatment of urinary bladder contractile dysfunction.

AIMS: We examined the potential stimulatory effects of U46619 (a prostanoid TP receptor agonist) and five prostanoids on the contractile activities of urinary bladder smooth muscle (UBSM), focusing on the role of the TP receptor and its associated Ca2+ influx routes to understand the roles of prostanoids in the regulation of UB contractile activity. MAIN METHODS: Changes in the basal tone and spontaneous contractile activity (amplitude and frequency) of isolated guinea pig UBSM were measured isotonically. The presence of TP receptors in UBSM was examined by RT-qPCR and immunofluorescence. KEY FINDINGS: U46619, prostaglandin (PG) E2, PGF2α, and PGA2 enhanced UBSM basal tone and spontaneous contractile activities, which were measured as amplitudes and frequencies. The enhancing effects of U46619 were completely suppressed by SQ 29,548 (a TP receptor antagonist), which also partially suppressed the stimulating effects of other prostanoids. The expression of TP receptors in UBSMs was verified at the mRNA and protein level. The enhancing effects of U46619 completely disappeared in Ca2+-free solution. U46619-enhanced basal tone was completely suppressed by verapamil, an inhibitor of voltage-dependent Ca2+ channels (VDCCs), and verapamil strongly decreased the spontaneous contraction frequency. The spontaneous contractions remaining in the presence of verapamil were strongly suppressed by SKF-96365 (an inhibitor of receptor-operated Ca2+ channels (ROCCs)/store-operated Ca2+ channels (SOCCs)), but not by LOE-908 (an inhibitor of ROCCs). SIGNIFICANCE: Prostanoids can enhance UBSM contractile activities and thus may be endogenous candidates for induction of detrusor overactivity. The TP receptor and TP-receptor-activated VDCCs/SOCCs are key molecules responsible for these effects.

Metformin abrogates the voiding dysfunction induced by prolonged methylglyoxal intake.

Methylglyoxal (MGO) is a reactive carbonyl species found at high levels in blood of diabetic patients. The anti-hyperglycemic drug metformin can scavenger MGO and reduce the formation of advanced glycation end products (AGEs). Here, we aimed to investigate if MGO-induced bladder dysfunction can be reversed by metformin. Male C57/BL6 mice received 0.5% MGO in drinking water for 12 weeks, and metformin (300 mg/kg, daily gavage) was given in the last two weeks. The bladder functions were evaluated by performing voiding behavior assays, cystometry and in vitro bladder contractions. MGO intake markedly elevated the levels of MGO and fluorescent AGEs in serum and reduced the mRNA expression and activity of glyoxalase (Glo1) in bladder tissues. Glucose levels were unaffected among groups. MGO intake also increased the urothelium thickness and collagen content of the bladder. Void spot assays in conscious mice revealed an increased void volume in MGO group. The cystometric assays in anesthetized mice revealed increases of basal pressure, non-voiding contractions frequency, bladder capacity, inter-micturition pressure and residual volume, which were accompanied by reduced voiding efficiency in MGO group. In vitro bladder contractions to carbachol, α,ß-methylene ATP and electrical-field stimulation were significantly greater in MGO group. Metformin normalized the changes of MGO and AGEs levels, Glo1 expression and activity, urothelium thickness and collagen content. The MGO-induced voiding dysfunction were all restored by metformin treatment. Our findings strongly suggest that the amelioration of MGO-induced voiding dysfunction by metformin relies on its ability to scavenger MGO, preventing its accumulation in blood.

Duodenal and proximal jejunal motility inhibition associated with bisacodyl-induced colonic high-amplitude propagating contractions.

Bisacodyl is a stimulant laxative often used in manometric studies of pediatric constipation to determine if it can initiate propulsive high-amplitude propagating contractions (HAPCs). Whereas the effects of bisacodyl infusion on colonic motility are well described, the effects of the drug on other regions of the gut after colonic infusion are not known. The aim of the present study was to characterize the effects of bisacodyl on both colonic and small bowel motility. Twenty-seven children (9.3 ± 1.2 yr) undergoing simultaneous high-resolution antroduodenal and colonic manometry were included. Small bowel and colonic motor patterns were assessed before and after colonic infusion of bisacodyl. Patients were divided into two groups: responders and nonresponders based on the presence of high-amplitude propagating contractions (HAPCs) after bisacodyl infusion. Nineteen patients were responders. A total of 188 postbisacodyl HAPCs was identified with a mean count of 10.4 ± 5.5 (range, 3-22), at a frequency of 0.6 ± 0.2/min and mean amplitude of 119.8 ± 23.6 mmHg. No motor patterns were induced in the small bowel. However, in the 19 responders the onset of HAPCs was associated with a significant decrease in small bowel contractile activity. In the nonresponders, there was no detectable change in small bowel motility after bisacodyl infusion. Bisacodyl-induced HAPCs are associated with a significant reduction in small bowel motility probably mediated by extrinsic sympathetic reflex pathways. This inhibition is potentially related to rectal distension, caused by the HAPC anal propulsion of colonic content.NEW & NOTEWORTHY The present study has shown, for the first time, that the presence of high-amplitude propagating contractions induced by bisacodyl is associated with a significant reduction in small bowel motility. These findings support of possible existence of a reflex pathway that causes inhibition of small bowel motility in response to rectal distension.

Successful Management of Urinary Bladder Clot with Intravesical Tissue Plasminogen Activator Infusion in a Cat.

A 5 yr old male neutered domestic shorthair with intermittent signs of urinary tract obstruction was suspected of having a blood clot in the urinary bladder secondary to trauma. The cat was hospitalized and received standard supportive therapy for urinary tract obstruction with urinary catheterization, with the addition of intravesical saline flushes in an attempt to promote bladder clot lysis. The cat was subsequently discharged after voluntary urination was observed. The cat was represented 28 hr after discharge because of clinical signs consistent with urinary tract obstruction. The cat was hospitalized and intravesical tissue plasminogen activator (tPA) infusions (0.5 mg of tPA in 10 mL of saline with 2 hr dwell time q 8 hr) were administered to break down the bladder clot (2.78 × 4.46 cm). Thirty-two hours after starting tPA, the clot was no longer visible on ultrasound. The cat was discharged with no recurrent symptoms in the subsequent 11 mo. This is the first report of tPA being used for dissolution of bladder clot in a cat. There were no observed complications, suggesting that intravesical instillation of tPA may be a safe and efficacious therapy in cats, similar to the previously reported successes in dogs and humans.

The pretreatment of rats with nebivolol ameliorates bladder contractile dysfunction caused by ischemia-reperfusion injury.

OBJECTIVE: The present study aimed to investigate the protective effect of nebivolol in the bladder isolated from rats exposed to ischemia-reperfusion (IR) injury. METHODS: Sprague-Dawley rats were divided into control, IR, and nebivolol+IR groups. In the nebivolol+IR group, nebivolol was administered (0.4 mg/kg, subcutaneous) in rats prior to IR insult. At the end of the experimental protocol, the urinary bladder was rapidly isolated and bladder strips were mounted in an organ bath. After the equilibration period, potassium chloride (KCl, 20-100 mM) or carbachol (0.01-10 µM) was cumulatively added to the organ bath to generate cumulative concentration-response curves (CCRCs). Oxidative stress and interleukin 6 (IL-6) levels were also evaluated in the bladder tissue. RESULTS: The CCRCs of KCl and carbachol were significantly reduced in the IR group compared to those of the control, and this inhibition was reversed by the pretreatment of rats with nebivolol (P < .05). The IR group's total antioxidant status was significantly lower with a concomitant increase in IL-6 levels than that of the control and nebivolol+IR groups (P < .05). CONCLUSIONS: The present study indicates that pretreatment of rats with nebivolol (0.4 mg/kg) could improve bladder contractile dysfunction caused by IR injury through suppression of increased oxidative stress and IL-6 levels.

Receptor GPR91 contributes to voiding function and detrusor relaxation mediated by succinate.

AIM: Succinate activates the receptor GPR91 identified in the bladder. The present study aims to unravel the mechanisms of bladder relaxation by succinate and how the receptor is involved in structural and functional changes of the bladder. METHODS: Physiological recordings of bladder function were carried out by cystometry and organ bath from C57BL/6 mice, homozygous GPR91-/- mice, and Sprague-Dawley (SD) rats. GPR91 expression was confirmed by polymerase chain reaction and tissue morphology was examined by light (Masson trichrome) and fluorescence microscopy. Nitric oxide (NO) and ATP secretion were measured. RESULTS: Bladders of GPR91 KO mice had a greater mass to body weight ratio with a thicker bladder wall compared to C57BL/6 mice. They also displayed increased basal and maximal bladder pressures, and decreased intercontraction intervals, bladder capacity, micturition volume, and compliance. During cystometry, bladders of SD rats and C57BL/6 mice instilled with succinate (10 mM) showed signs of relaxation while bladders of GPR91 KO mice were unresponsive. Similarly, in organ bath, succinate relaxed bladder strips preincubated with carbachol, except GPR91 KO ones. Relaxation was stronger in the presence of urothelium and independent of NO synthesis. Bladder strips from all mice groups showed similar responses to KCl, carbachol, and electrical stimulation. In vitro, succinate increased NO secretion in urothelial cell culture of both C57BL6 and GPR91 KO mice while ATP secretion was potently decreased by succinate in C57BL6 culture only. CONCLUSION: Succinate through GPR91 is essential to bladder structure and contraction. GPR91 relaxes the detrusor partially by decreasing urothelial ATP secretion.

Management of highly recurrent bladder neck contractures via transurethral resection combined with intra- and post-operative triamcinolone acetonide injections.

PURPOSE: To present our preliminary experience in managing patients with highly recurrent bladder neck contractures (BNCs) after transurethral resection of the prostate (TURP). METHODS: Between February 2015 and March 2018, 28 patients with highly recurrent BNCs who had failed multiple prior to endoscopic treatments were managed with transurethral resection and intra- and post-operative triamcinolone acetonide injections. The scar tissue was resected to the circular fiber at the bladder neck, and triamcinolone acetonide (2 mL, 40 mg/mL) was injected at the incision sites (8 points) using a cystoscopic injection needle. The cystoscopy-guided injections were repeated every four weeks for total three times after surgery. The patients were followed up at 3, 6, 12 months after surgery, and in July-August 2019. RESULTS: The recurrent interval before the treatments was 2.2 ± 1.2 months, without any BNC recurrence in the first 12 weeks after transurethral resection. The urinary flow rate increased significantly and was maintained during the follow-up period. Adequate voiding function was reported in 25 of 28 patients at a median follow-up of 2.8 (1.7, 3.9) years. One of the three patients with decreased urinary flow rate had underactive detrusor and no BNC recurrence. The complications were mild and tolerable. CONCLUSION: Transurethral resection of the scar tissue combined with intra- and post-operative triamcinolone acetonide injections resulted in a success rate of 92.9% in patients with highly recurrent BNC following TURP. It is a simple, safe, and effective treatment for highly recurrent BNCs.

[A case of surfer's myelopathy with serial imaging examination from early stage after onset].

Surfer's myelopathy is non-traumatic spinal cord injury which develops in beginner surfers. The patient was a 17-year-old female who developed severe paraplegia with bilateral sensory dysfunction below the groin and bladder/rectal dysfunctions after her first surfing lesson. A spinal-cord MRI performed six hours after onset revealed an intramedullary hyperintensity area from T8 to the conus medullaris on the T2 weighted images. Expansion of this hyperintensity area was observed on Day 3 and showed a reduction on Day 8. After providing intravenous methylpredonisolone, intravenous glycerol and intravenous edaravone, motor function and bladder/rectal functions began to improve after approximately three weeks. In this study, the expansion of the lesion in the early stages of the disease course was observed by sequential spinal MRI. Furthermore, a time lag between improvement according to imaging and improvement in symptoms was also observed.

Uroprotective mechanisms of natural products against cyclophosphamide-induced urinary bladder toxicity: A comprehensive review.

One of the widely used anticancer drugs for the treatment of various neoplasms is cyclophosphamide (CYP). The inactive prodrug CYP is metabolized by cytochrome P450 enzyme into active metabolites, phosphoramide mustard and acrolein. The accumulation of acrolein metabolite inside the urothelium results in hemorrhagic cystitis (HC) which is a urotoxic adverse effect associated with the use of CYP. To counteract the occurrence of HC induced by CYP, Mesna is usually used, with allergic reactions reported in some cases. Therefore, several natural products have drawn much attention as alternative safe therapies to reduce the urotoxicity produced from the use of CYP. This review will focus on certain uroprotective mechanisms related to some medicinal plants that are used to ameliorate the CYP-induced urotoxicity in experimental models. The mechanisms involving oxidative stress, inflammation, immune system, apoptosis, DNA fragmentation, uroplakins, purinergic signaling and muscarinic receptors, and CytoP450 metabolism are discussed.

Anagliptin, a dipeptidyl peptidase-4 inhibitor, improved bladder function and hemodynamics in rats with bilateral internal iliac artery ligation.

AIMS: To investigate the effect of anagliptin (Ana), a dipeptidyl peptidase-4 (DPP-4) inhibitor, on acute ischemia-induced bladder dysfunction in rats. METHODS: Eight-week-old female Wistar-ST rats were randomly assigned into four groups: (a) sham; (b) ligation (Lig); (c) Lig + Ana; and (d) Lig + Liraglutide (a glucagon-like peptide-1 [GLP-1] receptor agonist; Lira). Rats in the Lig, Lig + Ana, and Lig + Lira groups underwent ligature of the bilateral internal iliac arteries. Ana was orally administered mixed with the CE-2 diet. Lira was subcutaneously administered once a day. Blood glucose levels, plasma dipeptidyl peptidase 4 (DPP-4) activity, GLP-1 levels, and bladder function were measured in all groups. Bladder blood flow was measured in the sham, Lig, and Lig + Ana groups, 4 weeks postsurgery. RESULTS: No differences in blood glucose levels among the groups were observed. DPP-4 activity decreased in the Lig + Ana group (P < .01). GLP-1 levels in the Lig + Ana and Lig + Lira groups were higher than those in the sham and Lig groups (P < .01). Intercontraction intervals (ICIs) were longer in the Lig and Lig + Lira groups than in the sham group (P < .05), but similar to those observed in the Lig + Ana and sham groups. The Lig group exhibited reduced bladder blood flow relative to the sham group (P < .01); however, this measure improved in the Lig + Ana group (P < .01). CONCLUSIONS: Ana administration improved ICIs and bladder blood flow after acute bladder ischemia through a GLP-1 receptor-independent signaling pathway, without altering the blood glucose levels. Therefore, Ana dosing might be useful to prevent ischemia-induced bladder dysfunctions.

Improvement of lower urinary tract function by a selective serotonin 5-HT1A receptor agonist, NLX-112, after chronic spinal cord injury.

Spinal cord injury (SCI) above the lumbosacral level results in lower urinary tract dysfunction, including (1) detrusor hyperreflexia, wherein bladder compliance is low, and (2) a lack of external urethral sphincter (EUS) control, leading to detrusor-sphincter dyssynergia (DSD) with poor voiding efficiency. Experimental studies in animals have shown a dense innervation of serotonergic (5-HT) fibers and multiple 5-HT receptors in the spinal reflex circuits that control voiding function. Here, we investigated the efficacy of NLX-112 (a.k.a. befiradol or F13640), in regulating lower urinary tract function after T8 contusive SCI in rats. NLX-112 is a very potent, highly-selective, and fully efficacious 5-HT1A receptor agonist, which has been developed for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease patients. We performed urodynamics tests and external urethral sphincter electromyogram recordings to assess lower urinary tract function while NLX-112 was infused through the femoral vein in rats with chronic complete SCI or contusive SCI. The dose response studies indicated that NLX-112 was able to improve voiding behavior by regulating both detrusor and EUS activity. These included improvements in voiding efficiency, reduction of detrusor hyperactivity, and phasic activity of EUS during the micturition period. In addition, the application of a selective 5-HT1A receptor antagonist, WAY100635, reversed the improved detrusor and EUS activity elicited by NLX-112. In summary, the current data suggest that pharmacological activation of 5-HT1A receptors by NLX-112 may constitute a novel therapeutic strategy to treat neurogenic bladder after SCI.

The early, long-term inhibition of brain-derived neurotrophic factor improves voiding, and storage dysfunctions in mice with spinal cord injury.

AIMS: We examined the time course of urodynamic changes and the effect of the short or long-term inhibition of brain-derived neurotrophic factor (BDNF) from the early phase after spinal cord injury (SCI) in mice. METHODS: The spinal cord of female C57BL/6N mice was completely transected. We examined filling cystometry and bladder BDNF levels at 10, 20, and 30 days after SCI, with an additional day-5 measurement of BDNF. In a separate group of mice, anti-BDNF antibody (Ab) (10 µg/kg/h) was subcutaneously administered using osmotic pumps from day 3 after SCI, and single-filling cystometry was performed at 10 and 30 days (7 and 27 days of treatment, respectively) after SCI. RESULTS: Compared to spinal intact mice, bladder mucosal BDNF was increased at each time point after SCI with the maximal level at day 5 after SCI. Voiding efficiency was lower at each time point after SCI than that of spinal intact mice. The number of non-voiding contractions (NVC) during bladder filling was gradually increased with time. In both 10- and 30-day SCI groups treated with anti-BDNF Ab, voiding efficiency was improved, and the duration of notch-like intravesical pressure reductions during voiding bladder contractions was prolonged. The number of NVC was significantly decreased only in 30-day SCI mice with 27-day anti-BDNF treatment. CONCLUSIONS: Overexpression of BDNF is associated with the deterioration of voiding efficiency after SCI. The early-started, long-term inhibition of BDNF improved voiding dysfunction and was also effective to reduce the later-phase development of detrusor overactivity after SCI.

Magnesium and Bladder Discomfort after Transurethral Resection of Bladder Tumor: A Randomized, Double-blind, Placebo-controlled Study.

BACKGROUND: Catheter-related bladder discomfort occurs because of involuntary contractions of the bladder smooth muscle after urinary catheterization. Magnesium is associated with smooth muscle relaxation. This study hypothesized that among patients having transurethral resection of bladder tumor, magnesium will reduce the incidence of postoperative moderate-to-severe catheter-related bladder discomfort. METHODS: In this double-blind, randomized study, patients were randomly allocated to the magnesium group (n = 60) or the control group (n = 60). In magnesium group, a 50 mg/kg loading dose of intravenous magnesium sulfate was administered for 15 min, followed by an intravenous infusion of 15 mg · kg · h during the intraoperative period. Patients in the control group similarly received normal saline. The primary outcome was the incidence of catheter-related bladder discomfort above a moderate grade at 0 h postoperatively. None, mild, moderate, and severe catheter-related bladder discomfort at 1, 2, and 6 h postoperatively, patient satisfaction, and magnesium-related adverse effects were also assessed. RESULTS: The incidence of catheter-related bladder discomfort above a moderate grade at 0 h postoperatively was significantly lower in the magnesium group than in the control group (13 [22%] vs. 46 [77%]; P < 0.001; relative risk = 0.283; 95% CI, 0.171 to 0.467; absolute risk reduction = 0.55; number needed to treat = 2); similar results were observed for catheter-related bladder discomfort above a moderate grade at 1 and 2 h postoperatively (5 [8%] vs. 17 [28%]; P = 0.005; relative risk = 0.294; 95% CI, 0.116 to 0.746; and 1 [2%] vs. 14 [23%]; P < 0.001; relative risk = 0.071; 95% CI, 0.010 to 0.526, respectively). Patient satisfaction on a scale from 1 to 7 was significantly higher in the magnesium group than in the control group (5.1 ± 0.8 vs. 3.5 ± 1.0; P < 0.001; 95% CI, 1.281 to 1.919). Magnesium-related adverse effects were not significantly different between groups. CONCLUSIONS: Magnesium reduced the incidence of catheter-related bladder discomfort above a moderate grade and increased patient satisfaction among patients having transurethral resection of bladder tumor.

Therapeutic Effect of Botulinum Toxin A on Sensory Bladder Disorders-From Bench to Bedside.

Bladder oversensitivity arises from several different conditions involving the bladder, bladder outlet, systemic or central nervous system diseases. Increase of the bladder sensation results from activation of the sensory receptors in the urothelial cells or suburothelial tissues. Medical treatment targeting the overactive bladder (OAB) or interstitial cystitis (IC) might relieve oversensitive bladder symptoms (frequency, urgency and pain) in a portion of patients, but a certain percentage of patients still need active management. Botulinum toxin A (BoNT-A) has been demonstrated to have anti-inflammatory and antinociceptive effects in bladder sensory disorders and has been shown effective in the reduction of bladder oversensitivity and the increase of functional bladder capacity. For patients with OAB, urgency and urinary incontinence improved, while in patients with IC, bladder pain could be relieved in association with reduction of bladder oversensitivity after BoNT-A intravesical injection. Histological evidence has confirmed the therapeutic mechanism and clinical efficacy of intravesical BoNT-A injection on patients with OAB or IC. Bladder oversensitivity can also be relieved with the instillation of liposome encapsulated BoNT-A or low energy show waves (LESWs), which enable the BoNT-A molecule to penetrate into the urothelium and suburothelial space without affecting the detrusor contractility. Liposome encapsulated BoNT-A or combined LESWs and BoNT-A instillation might be future treatment alternatives for bladder oversensitivity in sensory bladder disorders.