Emodin inhibits bladder inflammation and fibrosis in mice with interstitial cystitis by regulating JMJD3

Purpose: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a devastating urological chronic pelvic pain condition. In search of a potential treatment, we investigated the effect of emodin on IC/BPS inflammation and fibrosis, and explore the potential mechanism. Methods: An experimental model of interstitial cystitis was induced by cyclophosphamide, and human bladder smooth muscle cells were treated with lipopolysaccharide to establish the cell model in vitro. In both models, inflammation- and fibrosis-related indexes were measured after emodin administration. Furthermore, the specific antagonists were used to dig for the mechanisms underlying the response to emodin treatment. Results: Emodin significantly ameliorated management of cystitis, reduced the amount of inflammatory cytokines (tumor necrosis factor-α, monocyte chemoattractant protein-1, interleukin-1ß, interleukin-8, and interleukin-6) in models, as well as reducing the synthesis of fibrosis marker including collagen1, collagen3, vimentin, fibronectin and α-smooth muscle actin. Further mechanism studies demonstrated that emodin inhibited inflammatory reaction and fibrosis through blocking lysine-specific demethylase 6B (JMJD3) expression via JAK/STAT, NF-κB and TGF-ß/SMAD pathways. Conclusions: Our study reveals the critical role of emodin-JMJD3 signaling in interstitial cystitis by regulating inflammation, fibrosis, and extracellular matrix deposition in cells and tissues, and these findings provide an avenue for effective treatment of patients with cystitis.

Aspectos psicológicos asociados a la cistitis intersticial / Psychological aspects associated with interstitial cystitis

La cistitis intersticial o síndrome de vejiga dolorosa es un padecimiento complejo asociado a dolor pélvico intenso con síntomas urinarios como urgencia, polaquiuria, dispareunia, incontinencia y nicturia, que afecta de manera importante la calidad de vida y las relaciones sociales y productivas del paciente. La evidencia muestra que el abordaje de los factores psicosociales que afectan a los pacientes con esta enfermedad es esencial. El tratamiento debe ir más allá de los síntomas clínicos y considerar los aspectos individuales de cada paciente, su salud mental, sus experiencias de vida y su comorbilidad, dado que los trastornos psicológicos como la ansiedad, la depresión y el estrés postraumático pueden influir en la manera en que se percibe el dolor, y están ligados con la gravedad y el empeoramiento de los síntomas. La literatura presenta a la intervención psicológica desde el enfoque cognitivo conductual como un medio para disminuir el dolor, la ansiedad y el catastrofismo, dando al paciente herramientas que le permitan obtener una sensación de control a partir del afrontamiento y mejorar su calidad de vida.

Interstitial cystitis or painful bladder syndrome is a complex condition associated with intense pelvic pain with urinary symptoms such as urgency, pollakiuria, dyspareunia, incontinence and nocturia that significantly affects the patient's quality of life, social and productive relationships. Evidence shows that addressing the psychosocial factors that affect patients with this disease is essential. Treatment should go beyond clinical symptoms and consider the individual aspects of each patient, their mental health, life experiences and comorbidities, since psychological disorders such as anxiety, depression and post-traumatic stress disorder can influence the way pain is perceived and are linked to the severity and worsening of symptoms. The literature presents psychological intervention from the cognitive-behavioral approach to reduce pain, anxiety and catastrophism, giving the patient tools that allow him to obtain a sense of control from coping tools that allow him to improve his quality of life.

Exploration of the core genes in ulcerative interstitial cystitis/bladder pain syndrome

ABSTRACT Objective: Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic inflammatory disease that can cause bladder pain and accompanying symptoms, such as long-term urinary frequency and urgency. IC/BPS can be ulcerative or non-ulcerative. The aim of this study was to explore the core genes involved in the pathogenesis of ulcerative IC, and thus the potential biomarkers for clinical treatment. Materials and Methods: First, the gene expression dataset GSE11783 was downloaded using the Gene Expression Omnibus (GEO) database and analyzed using the limma package in R to identify differentially expressed genes (DEGs). Then, the Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for Gene Ontology (GO) functional analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for pathway enrichment analysis. Finally, the protein-protein interaction (PPI) network was constructed, and key modules and hub genes were determined using the STRING and Cytoscape software. The resulting key modules were then analyzed for tissue-specific gene expression using BioGPS. Results: A total of 216 up-regulated DEGs and 267 down-regulated genes were identified, and three key modules and nine hub genes were obtained. Conclusion: The core genes (CXCL8, CXCL1, IL6) obtained in this study may be potential biomarkers of interstitial cystitis with guiding significance for clinical treatment.

Quality of life and related factors in patients with interstitial cystitis/bladder pain syndrome / 北京大学学报(医学版)

OBJECTIVE@#To evaluate the quality of life of patients with interstitial cystitis/bladder pain syndrome (IC/BPS), to compare the difference between IC/BPS and overactive bladder (OAB) pain syndrome, and to explore the related factors affecting the quality of life of IC/BPS patients.@*METHODS@#The demographic data of female outpatients with IC/BPS in Beijing Hospital and other medical centers in China were collected. The quality of life of the patients was investigated by multi-angle questionnaires and compared with the data of OAB patients. According to the influence degree of quality of life, the patients with IC/BPS were divided into mild-moderate group and severe group.@*RESULTS@#In this study, 109 patients with IC/BPS were included. The average age was (46.4±14.3) years and the average course of disease was (39.4±51.6) months. Compared with the OAB patients, the patients in IC/BPS group had a longer average course of disease (P=0.008), a lower proportion of the patients of first visit for the disease (P < 0.001), a higher score of the American Urological Association symptom index (AUA-SI) (P < 0.001), a lower body mass index (BMI) ratio (P=0.016), and a lower incidence of constipation (P=0.006). IC/BPS had the greatest impact on family life, followed by social activity. The score of IC/BPS related symptoms on family life was significantly higher than that of the OAB group (P=0.003). The top three symptoms of the IC/BPS patients were pain (45%), frequency (28%) and urgency (17%). The score of quality of life in the IC/BPS patients was significantly higher than that in the OAB patients (P < 0.001). Caffeine intake (P=0.034) and constipation (P=0.003) might be the factors influencing the quality of life of the patients with IC/BPS.@*CONCLUSION@#IC/BPS has a great influence on the quality of life of patients. Caffeine intake and constipation may be related factors affecting the quality of life of patients with IC/BPS. Urologists should recommend changes in diet and lifestyle to reduce symptoms and improve the patients' quality of life.

Intravesical Glycosaminoglycans Experience for Chronic Lower Urinary Tract Pathology Treatment / Experiencia con glucosaminoglicanos intravesicales para el tratamiento de patologías crónicas del tracto urinario inferior

Objective Intravesical glycosaminoglycans (GAG) treatment is one of the therapeutic options for chronic bladder pathologies and is approved for Bladder Pain Syndrome (BPS), radiation cystitis, and recurrent urinary tract infections (UTIs). The purpose of this study is to describe the demographic characteristics of patients with such pathologies in our population and to evaluate treatment response. Methods It is a retrospective study of patients with the aforementioned pathologies, who received treatment with GAG. Demographic characteristics and subjective improvement with treatment were evaluated. A bivariate analysis was performed to study possible improvement predictors. Results 53 patients were evaluated. Of them, 33 (62.3%) with BPS, 12 (22.6%) with recurrent UTIs, and 8 (15.1%) with radiation cystitis. The dose range received was between 4 - 20 instillations, with a median of 6 doses. 67.9% of patients showed improvement of symptoms with treatment, this percentage being even higher for the group of patients with recurrent UTIs (91%). No treatment response predictors were found. Conclusions Intravesical GAG treatment is a therapeutic alternative for patients with chronic bladder pathologies, with satisfactory results in the medium term. Prospective studies are needed to support the findings of this study.

Objetivo El tratamiento con glucosaminoglicanos intravesicales hace parte de las opciones terapéuticas de las patologías crónicas de la vejiga y se encuentra aprobado para el tratamiento de síndrome de vejiga dolorosa (SVD), cistitis por radiación e infección urinaria recurrente. El objetivo de este estudio es describir las características demográficas de los pacientes con dichas patologías en nuestra población y evaluar la respuesta al tratamiento. Métodos Estudio retrospectivo de pacientes con las patologías mencionadas, quienes recibieron tratamiento con glucosaminoglicanos. Se evaluaron las características demográficas y la respuesta al tratamiento. Se realizó un análisis bivariado para estudiar posibles variables predictoras de mejoría. Resultados Se evaluaron 53 pacientes. De estos, 33 (62.3%) con síndrome de vejiga dolorosa, 12 (22.6%) con infección urinaria recurrente y 8 (15.1%) con cistitis por radiación. El rango de dosis recibida estuvo entre 4-20 instilaciones, con una mediana de 6 dosis. El 67.9% de los pacientes tuvo una respuesta adecuada al tratamiento, siendo este porcentaje aún mayor para el grupo de pacientes con IVU recurrente (91%). No se encontraron factores predictores de respuesta al tratamiento. Conclusiones El tratamiento con GAG intravesicales es una alternativa terapéutica para pacientes con patologías crónicas de la vejiga, con resultados satisfactorios a mediano plazo. Se necesitan estudios prospectivos que soporten los hallazgos de este trabajo.

Interstitial cystitis - intravesical treatment

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.

Risk Factors for Interstitial Cystitis in the General Population and in Individuals With Depression / 대한배뇨장애요실금학회지

PURPOSE: To identify risk factors for interstitial cystitis (IC), a chronic bladder disorder that may have a significant detrimental impact on quality of life, in the general population and in individuals with depression. METHODS: This was a comparative study using a US claims database. Adults who had records of a visit to the health system in 2010 or later were included. The outcome was the development of IC within 2 years after the index date. The index date for the general population was the first outpatient visit, and for individuals with depression, it was the date of the diagnosis of depression. IC was defined using the concepts of ulcerative and IC. We included all medical conditions present any time prior to the index visit as potential risk factors. RESULTS: The incidence of IC was higher in individuals with depression than in the general population. Of the 3,973,000 subjects from the general population, 2,293 (0.06%) developed IC within 2 years. Of the 249,200 individuals with depression, 320 (0.13%) developed IC. The characteristics of the individuals who developed IC were similar in both populations. Those who developed IC were slightly older, more likely to be women, and had more chronic pain conditions, malaise, and inflammatory disorders than patients without IC. In the general population, subjects who developed IC were more likely to have mood disorders, anxiety, and hypothyroidism. CONCLUSIONS: The incidence of IC was higher in individuals with depression. Subjects who developed IC had more chronic pain conditions, depression, malaise, and inflammatory disorders.

Efficacy of electroacupuncture nerve stimulation therapy for interstitial cystitis/bladder pain syndrome / 中国针灸

OBJECTIVE@#To explore the clinical efficacy of electroacupuncture nerve stimulation therapy (ENST) for interstitial cystitis/painful bladder syndrome (IC/PBS).@*METHODS@#A total of 68 patients with IC/PBS were randomly divided into an observation group and a control group, 34 cases in each one. The patients in the observation group were treated with ENST; abdominal four acupoints and sacral four acupoints were connected with a pair of electrodes and treated alternately every other day. The ENST was given 50 min per times, three times a week for 3 months. The patients in the control group were treated with perfusion therapy of four-medication combination (heparin sodinm, lidocaine, sodium bicarbonate, gentamicin sulfate), twice a week for the first 6-8 weeks, followed by twice per month for 3 months. The infusion fluid remained for 1 h before discharging. The O' Leary-Sant score, including interstitial cystitis symptom index (ICSI) and interstitial cystitis problem index (ICPI), 24 h urination frequency, visual analogue scale (VAS) and maximum bladder volume were observed before treatment and treatment of 1 month, 3 months and 6 months after treatment respectively; the adverse events during the treatment were also recorded.@*RESULTS@#Compared before treatment, the O'Leary-Sant score (ICSI, ICPI), 24 h urination frequency, VAS and maximum bladder volume in the two groups were improved after 1, 3 months treatment and 6 months after treatment (all <0.05). The scores of ICSI, ICPI, VAS and 24 h urination frequency in the observation group were significantly lower than those in the control group (<0.05). The maximum bladder volume in the observation group was significantly higher than that in the control group (<0.05). Six months after treatment, the total effective rate in the observation group was 87.5% (28/32), which was higher than 69.7% (23/33) in the control group (<0.01). No significant adverse events occurred during the treatment.@*CONCLUSION@#ENST could effectively relieve the clinical symptoms of IC/PBS, but its long-term efficacy needs further observation.

Therapeutic Endoscopic Treatment Plus Maintenance Dimethyl Sulfoxide Therapy Prolongs Recurrence-Free Time in Patients With Hunner Type Interstitial Cystitis: A Pilot Study / 대한배뇨장애요실금학회지

PURPOSE: To evaluate whether hydrodistention with fulguration of Hunner lesions (HD/FUL) plus maintenance dimethyl sulfoxide (DMSO) therapy prolongs the recurrence-free time in patients with Hunner type interstitial cystitis (IC).METHODS: The study enrolled patients with Hunner type IC who required repeat HD/FUL due to recurrence of IC symptoms after the first HD/FUL at our institution. All patients received a second HD/FUL plus maintenance DMSO therapy. The maintenance DMSO therapy was performed every 2 weeks for a total of 8 instillations, and then once every 4 weeks thereafter. The recurrencefree time from HD/FUL to therapeutic failure was estimated using the Kaplan-Meier method. The recurrence-free time between the first HD/FUL and second HD/FUL plus maintenance DMSO therapy was statistically compared using the log-rank test.RESULTS: A total of 21 patients (mean age, 66.3±10.8 years) with Hunner type IC were evaluated. The recurrence-free time for the second HD/FUL plus maintenance DMSO therapy was significantly longer than that for the first HD/FUL (P<0.0001). The median recurrence-free time for the first HD/FUL was 10.1 months, while that for the second HD/FUL plus maintenance DMSO therapy has yet to be reached. The recurrence-free rate for the first HD/FUL was 81.0% at 6 months, 38.1% at 1 year, 9.5% at 2 years, and 4.8% at 3 years. In contrast, the rate for the second HD/FUL plus maintenance DMSO therapy was 100% at 6 months, 94.7% at 1 year, 82.6% at 2 years, and 82.6% at 3 years. There were no significant differences in efficacy between the first and second HD/FUL.CONCLUSIONS: HD/FUL plus maintenance DMSO therapy clearly prolongs the recurrence-free time compared with HD/FUL alone in Hunner type IC.

Impact of intravesical hyaluronic acid treatment on bladder inflammation in interstitial cystitis rat model

ABSTRACT Objective: To evaluate the effect of intravesical hyaluronic acid (HA) treatment on inflammatory cells and the severity of inflammation in an interstitial cystitis rat model created with hydrogen chloride (HCL) via immunohistochemical studies and myeloperoxidase activity for the first time in the literature. Materials and Methods: A total of 30 adult female white Rattus Norvegicus rats were divided into 3 groups as the HCL group, hyaluronic acid treatment (HCL-HA) group and control group. Chemical cystitis was created by administering HCL(400 microL,10 mM) except control group. A single dose of intravesical HA(0.5 mL,0.8 mg/mL) was administered to the treatment group. The bladder tissues of all subjects were immunohistochemically stained. The cell surface markers were used to evaluate inflammatory cell infiltration. Mast cell activation and IL-6 was evaluated to assess the inflammation and severity of inflammation, respectively. Myeloperoxidase activity was measured as it shows neutrophil density. Statistical significance was accepted as P<0.05. Results: It was observed that there was rich monocyte, T lymphocyte, B lymphocyte, and Natural Killer cells infiltration and high IL-6 levels in the bladder tissue after the intravesical hydrogen chloride instillation, especially in the stroma layer(p<0.005). In the HCL-HA group, severity of inflammation had statistically significantly regressed to the levels of the control group(p<0.005). An increase was observed in the bladder myeloperoxidase activity of the HCL group compared to the other two groups(p<0.05). Conclusions: Single dose intravesical hyluronic acid instillation reduces inflammatory cell infiltration and the severity of bladder inflammation in the rat model of bladder pain syndrome/interstitial cystitis.

Systematic review of oral therapy for the treatment of symptoms of bladder pain syndrome: The brazilian guidelines / Revisão sistemática sobre terapia oral para tratamento dos sintomas da síndrome da bexiga dolorosa: as diretrizes brasileiras

Abstract Interstitial cystitis (IC), including bladder pain syndrome (BPS), is a chronic and debilitating disease thatmainly affectswomen. It is characterized by pelvic pain associated with urinary urgency, frequency, nocturia and negative urine culture,with normal cytology. In 2009, the Society for Urodynamics and Female Urology (SUFU) defined the term IC/BPS as an unpleasant sensation (pain, pressure, and discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms for more than 6 weeks duration, in the absence of infection or other identifiable causes. This is the definition used by the American Urological Association (AUA) in the most recent guidelines on IC/BPS. Interstitial cystitis may be sufficiently severe to have a devastating effect on the quality of life, but it may also be associated with moderate symptoms whose effects are less debilitating. Although there are several clinical trials to assess oral and intravesical therapies, the treatment for IC remains far from ideal. This systematic assessment evaluates published randomized clinical trials on oralmedications used totreat symptoms of BPS. This studywas performed according to the preferred reporting items for systematic reviews and metaanalyses (PRISMA)method. Two independent reviewers screened the studies to determine their inclusion or exclusion and to perform the methodological analysis. The inclusion criteria included randomized studiespublishedbetween April of 1988and April of2016 that used oral medications to treat symptoms of BPS or IC. According to the systematic review performed,we should consider pentosan polysulfate as one of the bestoptions of oral drugs for the treatment of BPS symptoms. However, this drug is not an available option in Brazil. Orally administered amitriptyline is an efficacious medical treatment for BPS, and it should be the first treatment offered.

Resumo Cistite intersticial (IC), incluindo a síndrome da bexiga dolorosa (SBD), é uma doença crônica e debilitante que afeta principalmente mulheres. É caracterizada por dor pélvica associada à urgência miccional, frequência urinária, noctúria e exame cultural de urina negativo, com citologia normal. A cistite intersticial pode ser suficientemente severa para ter um efeito devastador na qualidade de vida, mas também pode estar associada a sintomas moderados e menos debilitantes. Embora existam vários ensaios clínicos para avaliar terapias orais e intravesicais, o tratamento para IC permanece longe do ideal. Esta revisão sistemática avaliou ensaios clínicos randomizados publicados sobre medicamentos orais usados para tratar sintomas de SBD. Este estudo foi realizado de acordo com ométodo preferred reporting items for systematic reviews and meta-analyses (PRISMA). Dois revisores independentes examinaram os estudos para determinar sua inclusão ou exclusão e para realizar a análise metodológica. Os critérios de inclusão foram: ensaios clínicos randomizados publicados entre abril de 1988 e abril de 2016 que usaram medicações orais no tratamento dos sintomas da SBD ou CI. De acordo com a revisão sistemática realizada, a melhor opção de medicação oral para o tratamento dos SBD é o pentosano polissulfato sódico. No entanto, esta droga não está disponível no Brasil. A amitriptilina administrada por via oral é um tratamento eficaz para SBD e deve ser oferecida como primeira escolha.

Animal Modelling of Interstitial Cystitis/Bladder Pain Syndrome / 대한배뇨장애요실금학회지

The etiology of interstitial cystitis/bladder pain syndrome (IC/BPS) remains elusive and may involve multiple causes. To better understand its pathophysiology, many efforts have been made to create IC/BPS models. Most existing models of IC/BPS strive to recreate bladder-related features by applying noxious intravesical or systemic stimuli to healthy animals. These models are useful to help understand various mechanisms; however, they are limited to demonstrating how the bladder and nervous system respond to noxious stimuli, and are not representative of the complex interactions and pathophysiology of IC/BPS. To study the various factors that may be relevant for IC/BPS, at least 3 different types of animal models are commonly used: (1) bladder-centric models, (2) models with complex mechanisms, and (3) psychological and physical stressors/natural disease models. It is obvious that all aspects of the human disease cannot be mimicked by a single model. It may be the case that several models, each contributing to a piece of the puzzle, are required to recreate a reasonable picture of the pathophysiology and time course of the disease(s) diagnosed as IC/BPS, and thus to identify reasonable targets for treatment.

Differences in Urodynamic Parameters According to the Presence of a Hunner Lesion in Women With Interstitial Cystitis/Bladder Pain Syndrome / 대한배뇨장애요실금학회지

PURPOSE: Differences in the severity of subjective symptoms have been noted depending on whether a Hunner lesion is present in women with interstitial cystitis/bladder pain syndrome (IC/BPS). In this study, we aimed to identify differences in objective urodynamic parameters in women with IC/BPS according to the presence of a Hunner lesion. METHODS: This cross-sectional study included a total of 55 patients with IC/BPS. IC/BPS and the presence of a Hunner lesion on cystoscopy were diagnosed according to American Urological Association guidelines. The patients were categorized into a Hunner IC/BPS group and a non-Hunner IC/BPS group according to the presence of a Hunner lesion on cystoscopy. At the initial visit, a medical history was taken from all patients with IC/BPS, and they underwent symptom assessment using a 3-day voiding diary and laboratory tests. A urodynamic study was then performed before any treatment was performed. Baseline characteristics and urodynamic parameters were compared between the 2 groups. RESULTS: Of the 55 patients, 23 (41.8%) had a Hunner lesion on cystoscopy. As documented in the voiding diaries, the Hunner IC/BPS group had more frequent voids and a smaller maximal voided volume (P=0.045, P < 0.001, respectively). Regarding urodynamic parameters, the mean volume at the first desire to void, normal desire to void, strong desire to void (SDV), and maximum cystometric bladder capacity (MBC) was significantly lower in the Hunner IC/BPS group (P=0.001, P=0.004, P < 0.001, and P < 0.001, respectively). On receiver operating characteristic curve analysis, patients with an SDV≤210 mL (area under the curve [AUC]=0.838, P < 0.001) and an MBC≤234 mL (AUC=0.857, P < 0.001) were likely to be in the Hunner IC/BPS group. CONCLUSIONS: The differences in patients’ subjective symptoms between the Hunner IC/BPS and non-Hunner IC/BPS groups were confirmed to correspond to differences in objective urodynamic parameters.

Feline Interstitial Cystitis Enhances Mucosa-Dependent Contractile Responses to Serotonin / 대한배뇨장애요실금학회지

PURPOSE: To determine whether responses to serotonin are altered in bladder strips from cats diagnosed with a naturally occurring form of bladder pain syndrome/interstitial cystitis termed feline interstitial cystitis (FIC). METHODS: Full thickness bladder strips were isolated from aged matched healthy control cats and cats with clinically verified FIC. Bladder strips were mounted in an organ bath and connected to a tension transducer to record contractile activity. A serotonin dose response (0.01–10μM) was determined for each strip with the mucosa intact or denuded. RESULTS: Bladder strips from control and FIC cats contracted in response to serotonin in a dose-dependent manner. The normalized force of serotonin-evoked contractions was significantly greater in bladder strips from cats with FIC (n=7) than from control cats (n=4). Removal of the mucosa significantly decreased serotonin-mediated responses in both control and FIC bladder preparations. Furthermore, the contractions in response to serotonin were abolished by 1μM atropine in both control and FIC bladder strips. CONCLUSIONS: The effect of serotonin on contractile force, but not sensitivity, was potentiated in bladder strips from cats with FIC, and was dependent upon the presence of the mucosa in control and FIC groups. As atropine inhibited these effects of serotonin, we hypothesize that, serotonin enhances acetylcholine release from the mucosa of FIC cat bladder strips, which could account for the increased force generated. In summary, FIC augments the responsiveness of bladder to serotonin, which may contribute to the symptoms associated with this chronic condition.

Neonatal Bladder Irritation Is Associated With Vanilloid Receptor TRPV1 Expression in Adult Rats / 대한배뇨장애요실금학회지

PURPOSE: To evaluate whether mild chemical irritation of the bladder in neonatal rats is associated with persistent vanilloid receptor transient receptor potential vanilloid subfamily 1 (TRPV1) activity in adult rats. METHODS: Female Sprague-Dawley rats were used. Ten-day-old rat pups underwent bladder sensitization via intravesical infusion of 0.2% acetic acid in saline with or without prior bladder desensitization with capsaicin. After 8 weeks, 3 groups of rats (control [group 1], bladder sensitization [group 2], and bladder desensitization [group 3]) underwent cystometry. Inflammation of bladder tissue and the expression of TRPV1 in bladder tissue and dorsal root ganglia (DRG) were also evaluated. RESULTS: The bladder sensitization group showed more frequent voiding contractions. TRPV1 expression in adult bladder tissue was elevated in group 2. TRPV1 mRNA levels in the bladder and DRG were significantly higher in group 2 than in group 1. Moreover, group 2 had significantly more DRG neurons (identified by uptake of the retrograde label Fast Blue) that exhibited TRPV1 immunoreactivity. CONCLUSIONS: We found a significant association between neonatal bladder sensitization and persistent TRPV1 activity in adult rats. This is the first study to focus on the underlying pathogenesis of bladder overactivity from childhood to adulthood. Our findings could lead to the development of new strategies for the treatment and prevention of adult urinary symptoms arising from childhood urinary tract dysfunction.

A prospective randomized controlled multicentre trial comparing intravesical DMSO and chondroïtin sulphate 2% for painful bladder syndrome/interstitial cystitis

ABSTRACT Objective To compare effectiveness of intravesical chondroïtin sulphate (CS) 2% and dimethyl sulphoxide (DMSO) 50% in patients with painful bladder syndrome/interstitial cystitis (PBS/IC). Materials and methods Patients were randomized to receive either 6 weekly instillations of CS 2% or 50% DMSO. Primary endpoint was difference in proportion of patients achieving score 6 (moderately improved) or 7 (markedly improved) in both groups using the Global Response Assessment (GRA) scale. Secondary parameters were mean 24-hours frequency and nocturia on a 3-day micturition dairy, changes from baseline in O’Leary-Sant questionnaire score and visual analog scale (VAS) for suprapubic pain. Results Thirty-six patients were the intention to treat population (22 in CS and 14 in DMSO group). In DMSO group, 57% withdrew consent and only 6 concluded the trial. Major reasons were pain during and after instillation, intolerable garlic odor and lack of efficacy. In CS group, 27% withdrew consent. Compared with DMSO group, more patients in CS group (72.7% vs. 14%) reported moderate or marked improvement (P=0.002, 95% CI 0.05-0.72) and achieved a reduction in VAS scores (20% vs. 8.3%). CS group performed significantly better in pain reduction (-1.2 vs. -0.6) and nocturia (-2.4 vs. -0.7) and better in total O’Leary reduction (-9.8 vs. -7.2). CS was better tolerated. The trial was stopped due to high number of drop-outs with DMSO. Conclusions Intravesical CS 2% is viable treatment for PBS/IC with minimal side effects. DMSO should be used with caution and with active monitoring of side effects. More randomized controlled studies on intravesical treatments are needed.

Current Pharmacologic Approaches in Painful Bladder Research: An Update / 대한배뇨장애요실금학회지

The symptoms of interstitial cystitis (IC)/bladder pain syndrome (BPS) may have multiple causes and involve many contributing factors. Traditional treatments (intravesical instillations) have had a primary focus on the bladder as origin of symptoms without adequately considering the potential influence of other local (pelvic) or systemic factors. Systemic pharmacological treatments have had modest success. A contributing factor to the low efficacy is the lack of phenotyping the patients. Individualized treatment based on is desirable, but further phenotype categorization is needed. There seems to be general agreement that IC is a unique disease and that BPS is a syndrome with multiple pathophysiologies, but this has so far not been not been well reflected in preclinical research with the aim of finding new pharmacological treatments. Current research approaches, including anti-nerve growth factor treatment, anti-tumor necrosis factor-α treatment, activation of SHIP1 (AQX-1125), and P2X3 receptor antagonists, and α1-adrenoceptor antagonists are potential systemic treatments, implying that not only the bladder is exposed to the administered drug, which may be beneficial if the IC/BPS is a bladder manifestation of a systemic disease, or negative (adverse effects) if it is a local bladder condition. Local treatment approaches such as the antagonism of Toll-like receptors (which still is only experimental) and intravesical liposomes (with positive proof-of-concept), may have the advantages of a low number of systemic adverse effects, but cannot be expected to have effects on symptoms generated outside the bladder. Assessment of which of the treatment approaches discussed in this review that can be developed into useful therapies requires further studies.

Comparison of 5 Different Rat Models to Establish a Standard Animal Model for Research Into Interstitial Cystitis / 대한배뇨장애요실금학회지

PURPOSE: We evaluated 5 different rat models using different agents in order to establish a standard animal model for interstitial cystitis (IC) in terms of the functional and pathologic characteristics of the bladder. METHODS: Five IC models were generated in 8-week-old female Sprague-Dawley rats via transurethral instillation of 0.1M hydrogen chloride (HCl) or 3% acetic acid (AA), intraperitoneal injection of cyclophosphamide (CYP) or lipopolysaccharide (LPS), or subcutaneous injection of uroplakin II (UPK2). After generating the IC models, conscious cystometry was performed on days 3, 7, and 14. All rats were euthanized on day 14 and their bladders were obtained for histological and pro-inflammatory-related gene expression analysis. RESULTS: In the cystometric analysis, all experimental groups showed significantly decreased intercontraction intervals compared with the control group on day 3, but only the LPS and UPK groups maintained significantly shorter intercontraction intervals than the control group on day 14. The histological analysis revealed that areas with severe urothelial erosion (HCl, AA, and UPK) and hyperplasia (CYP and LPS), particularly in the UPK-treated bladders, showed a markedly increased infiltration of toluidine blue-stained mast cells and increased tissue fibrosis. In addition, significantly elevated expression of interleukin-1b, interleukin-6, myeloperoxidase, monocyte chemotactic protein 1, and Toll-like receptors 2 and 4 was observed in the UPK group compared to the other groups. CONCLUSIONS: Among the 5 different agents, the injection of UPK generated the most effective IC animal model, showing consequent urothelial barrier loss, inflammatory reaction, tissue fibrosis stimulation, and persistent hyperactive bladder.