The effects of a galectin-3 inhibitor on bladder pain syndrome in mice with cyclophosphamide-induced cystitis.

AIMS: To explore the effect of blocking galectin-3 in the bladder pain syndrome associated with interstitial cystitis. METHODS: A galectin-3 inhibitor was used to treat mice with cyclophosphamide-induced cystitis. The expression of galectin-3 in bladder tissues and urine was examined by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), respectively. Suprapubic-pelvic pain, bladder voiding, bladder pain-like nociceptive behavior, and referred hyperalgesia were assessed. The weights of the bladders were also measured, and inflammatory cell infiltration and inflammatory cytokine levels were examined by histopathological evaluation. The inflammatory cytokines interleukin 1ß (IL-1ß), nerve growth factor (NGF), IL-6, and tumor necrosis factor α (TNF-α) were measured by ELISA. RESULTS: Increases in galectin-3 levels, inflammation, bladder weight, and bladder pain-related symptoms were observed in bladders with cyclophosphamide-induced cystitis. Administration of the galectin-3 inhibitor significantly mitigated bladder pain-related symptoms and inflammatory response. In response to the 500 µM dose of the galectin-3 inhibitor, nociceptive behaviors, nociceptive score, and bladder-to-body weight ratios were reduced by 65.1%, 65.3%, and 40.3%, respectively, while 500 µM Gal-3 inhibitor increased pelvic pain threshold by 86.7%. Moreover, galectin-3 inhibitor treatment inhibited the inflammation. Compared to untreated CYP-induced mice, there were significant changes in the levels of IL-1ß (41.72 ± 2.05 vs. 18.91 ± 2.26 pg/mg tissues), NGF (9.64 ± 0.38 vs. 1.88 ± 0.05 pg/mg tissues), IL-6 (42.67 + 1.51 vs. 21.26 + 2.78 pg/mg tissues, and TNF-α (22.02 ± 1.08 vs. 10.70 ± 0.80 pg/mg tissues) in response to the highest dose of the Gal-3 inhibitor subgroup (500 µM), and 500 µM Gal-3 inhibitor reduced mast cell infiltration ratios by 71.8%. CONCLUSIONS: The galectin-3 inhibitor relieved pelvic pain, urinary symptoms, and bladder inflammation in mice with cyclophosphamide-induced cystitis. Thus, galectin-3 inhibitors may be novel agents in interstitial cystitis treatment.

Choreito, a Kampo medicine attenuates detrusor overactivity and bladder pain symptoms in rat tranilast-induced interstitial cystitis/bladder pain syndrome-like model.

AIMS: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory condition of the bladder. However, there are only a few medicines that are of pharmaceutical grade and reliably effective for IC/BPS symptoms. Choreito (CRT) is a pharmaceutical-grade Kampo medicine and has been widely prescribed for patients of lower urinary tract symptoms (LUTS) and BPS in Japan. In this study, we exploratory investigated the effects of CRT on the IC/BPS-like symptoms induced by tranilast. METHODS: The rat IC/BPS-like model was induced by feeding administration with 0.4% tranilast. The rats were divided into the three following treatment groups: normal diet (Normal), tranilast treatment (Control), and the groups of 1% CRT (CRT) treatment for IC/BPS-like model. After 4 weeks, continuous cystmetry, locomotor, and vascular permeability was assessed. Furthermore, the cytokine levels in bladder were analyzed by the Bio-Plex suspension array system and plasma monoamine were measured. RESULTS: Control group exhibited 14.3% decrease of locomotor activity in the dark period, and which were 20.3% increase by 1%CRT treatment. The voiding interval was shorter in control than in other groups. 1%CRT suppressed the shortening of voiding interval. Evans blue leakage of bladder wall observed 44.8% higher in control group than in the normal group. The leakage of 1%CRT group was 33.3% less than in the control group. The cytokine level of IFNγ and VEGF were elevated in the control, and CRT treatment suppressed the elevation of IFNγ in the bladder. Plasma noradrenaline was significantly reduced by CRT treatment compared normal group. CONCLUSION: These results suggest that CRT can be an effective therapeutic agent for the treatment of IC/BPS-like symptoms.

Pentosan polysulfate and a pigmentary maculopathy: causation versus correlation?

INTRODUCTION: Interstitial cystitis (IC) is a chronic disease with urinary tract symptoms and pain. Pentosan polysulfate (PPS) is the only U.S. Food and Drug Administration approved oral medication for the treatment of IC pain and symptoms. Recently, articles described a pigmentary maculopathy in IC patients on long term PPS therapy. Currently, there is no definitive study directly linking PPS as the cause of the pigmentary maculopathy. The aim of this review is to evaluate if PPS is the causative factor of the pigmentary maculopathy or if PPS use is only associated with the pigmentary maculopathy. MATERIALS AND METHODS: A comprehensive review of peer reviewed journals using the search terms IC, maculopathy, mast cells, immune inflammatory components, Tamm-Horsfall protein, cations and tight junctions was performed to examine the pathophysiology and role of chronic inflammation in IC and known retinal maculopathies. RESULTS: Chronic inflammatory cells have been reported in age-related macular degeneration choroid blood vessels and in bladder submucosal and detrusor layers in IC patients. Studies in IC and maculopathies demonstrate a significant milieu of activated chronic inflammatory and immunologic responses that cause a more "leaky" epithelium and a subsequent cascade of inflammatory events that results in the pathological changes seen in these two conditions. CONCLUSIONS: After an analysis of the literature describing a pigmentary maculopathy in IC patients on long term PPS, a causal relationship does not appear to be present. An alternate model is proposed postulating that the causative factor for the pigmentary maculopathy is the underlying inflammatory state associated with IC and not PPS use.

Uroprotective Potential of Campesterol in Cyclophosphamide Induced Interstitial Cystitis; Molecular Docking Studies.

Cyclophosphamide (CYP) is commonly used to treat cancer of the ovaries, breast, lymph, and blood system and produces interstitial cystitis (IC) via its urotoxic metabolite: i. e., acrolein. The present study was aimed to investigate the uroprotective effect of campesterol (a steroidal phytochemical) in cyclophosphamide induced IC. IC was induced by CYP (150 mg/kg, i. p.) in rats. The Enzyme linked immunosorbent assays for oxidative stress markers and Polymerase Chain Reaction (PCR) for inflammatory cytokines were carried out. The Tissue Organ Bath Technique was used for the evaluation of the spasmolytic effect of campesterol. Different pharmacological antagonists have been used to explore the mechanism of action of campesterol. Treatment with campesterol (70 mg/kg) reduced nociception (55 %), edema (67 %), hemorrhage (67 %), and protein leakage significantly (94 %). The antioxidant activity of campesterol was exhibited by a fall in MDA, NO, and an elevation in SOD, CAT, and GPX levels. Campesterol presented anti-inflammatory potential by decreasing IL-1, TNF-α, and TGF-ß expression levels. Histologically, it preserved urothelium from the deleterious effect of CYP. Campesterol showed a spasmolytic effect by reducing bladder overactivity that was dependent on muscarinic receptors, voltage-gated calcium and KATP channels, and cyclo-oxygenase pathways. In silico studies confirmed the biochemical findings. The findings suggest that campesterol could be valorized as a possible therapeutic agent against cyclophosphamide-induced interstitial cystitis.

Risk of maculopathy with pentosan polysulfate sodium use.

AIMS: Recent epidemiologic studies have examined the risk of maculopathy with pentosan polysulfate sodium (PPS), a drug indicated for the treatment of interstitial cystitis. However, results have been contradictory. Thus, we quantified the risk of maculopathy with PPS with a focus on risk with duration of use. METHODS: We used a new user, retrospective cohort study with an active comparator. We created a cohort of mutually exclusive 6221 PPS users and 89 744 amitriptyline users, a tricyclic antidepressant also used for the treatment of pain secondary to interstitial cystitis. Subjects were selected from the PharMetrics Plus database (IQVIA, Durham, NC) from 2006 to 2020. Cohort members were followed to the first event of the study outcome (maculopathy) or end of enrolment. A Cox regression model was constructed to adjust for potential confounders. RESULTS: The mean follow-up was 3.0 years for PPS users and amitriptyline users. The adjusted hazard ratio (HR) for maculopathy in PPS users was 2.64 (95% confidence interval [CI]: 1.90-3.68). The HR for the sensitivity analysis that combined maculopathy and age-related macular degeneration (AMD) was 1.38 (95% CI: 1.16-1.65). A cumulative duration-response pattern was observed, with use greater than 3 years having a 9.5-fold risk of maculopathy (HR = 9.56, 95% CI: 3.60-25.37) compared to a 2.3-fold risk of maculopathy with use for 1 year or less (HR = 2.27, 95% CI: 1.50-3.43). The number needed to harm for the first 4 years of use was 250. CONCLUSIONS: The results of this study suggest an increased risk of maculopathy with PPS use, particularly with longer duration of use.

[Urodynamic and histological evaluation of cyclophosphamide-induced bladder pain syndrome in SD rats].

OBJECTIVE: To establish a model of bladder pain syndrome in SD rats by cyclophosphamide intraperitoneal injection, to evaluate the effectiveness of the model from the urodynamic and histological levels, to lay a zoological foundation for the clinical study of bladder pain syndrome, and to further guide clinical treatment. METHODS: Thirty-two 8-week-old SD rats were randomly divided into 4 groups, including acute test group, acute control group, chronic test group, and chronic control group, with 8 rats in each group. The acute test group received intraperitoneal injection of cyclophosphamide 150 mg/kg immediately after the measurement of urodynamic data on the first day, and urodynamic examination was performed again 2 days later. After that, the rats were sacrificed to obtain bladder tissue. In the chronic test group, after measuring the baseline data of urodynamics on the first day, cyclophosphamide 75 mg/kg was intraperitoneally injected on the first, fourth, and seventh days, and the rats were sacrificed after measuring the urodynamic data again on the eighth day to obtain bladder tissue. The acute control group and the chronic control group were injected with the same amount of normal saline during intraperitoneal injection, and the urodynamic testing time point were consistent with the corresponding test groups. Histopathological changes of the bladder were assessed by HE staining. RESULTS: In each acute and chronic group, there were no intragroup differences in baseline urodynamic levels between the test and control groups. The urodynamic maximum bladder volume was significantly reduced in the acute test group after administration(t=-2.961, P < 0.05), histologically, severe interstitial edema, obvious inflammatory cell infiltration, mucosal edema and submucosal hemorrhage, and partial urothelium were absent could be seen, which were consistent with acute cystitis performance. The urodynamic maximum bladder capacity was significantly reduced in the chronic test group after administration (t=-3.886, P < 0.05), and the bladder compliance was lower than that in the control group, but not significant, the histological manifestations were urothelial exfoliation, interstitial edema, submucosal hemorrhage, infiltration of inflammatory cells such as lymphocytes, and dense vascular distribution. CONCLUSION: In the acute test group, a single intraperitoneal injection of cyclophosphamide could induce acute bladder inflammation in the rats. In the chronic test group, repeated injections of cyclophosphamide could induce histological changes in chronic inflammation of chronic bladder pain syndrome in the rats. But the bladder function was not significantly impaired.

Identification of key genes in human urothelial cells corresponding to interstitial cystitis/bladder pain syndrome in a lipopolysaccharide-induced cystitis model.

AIMS: The cellular functions of bladder urothelial cells in interstitial cystitis/bladder pain syndrome (IC/BPS) have not been well revealed and understood. Thus, the study aims to identify key genes and significant pathways in urothelium corresponding to IC/BPS in a lipopolysaccharide (LPS)-induced cystitis model and provide novel clues related to diagnosis and treatment of IC/BPS. METHODS: Human urothelial cells (HUCs) were incubated with LPS (50 µg/ml for 24 h). Microarray was applied to analyze the differentially expressed genes (DEGs) between HUCs under LPS treatment and the control group. DEGs in the two groups were identified and then used for enrichment analysis. Subsequently, protein-protein interaction (PPI) network based on DEGs was constructed. Lastly, the top five key genes were identified through the Cytoscape (version 3.7.2) using the "Clustering Coefficient" algorithm. RESULTS: One hundred and seventy-one DEGs (96 upregulated genes and 75 downregulated genes) were identified between the LPS treatment and control group. The established PPI network was composed of 169 nodes and 678 edges. Moreover, C19orf33, TRIM31, MUC21, ELF3, and IFI27 were identified as hub genes in the PPI network. Subsequently, a statistically increased expression level of TRIM31 and ELF3 was validated by real-time quantitative-polymerase chain reaction and immunohistochemistry in bladder tissues from 20 patients with IC/BPS. CONCLUSIONS: TRIM31 and ELF3 may be the two hub genes in urothelium corresponding to IC/BPS. More studies are warranted to further validate the findings. The identified marker genes may be useful targets for further studies to develop diagnostic tools and more effective therapies for a broader group of women with IC/PBS.

Beneficial effect of Bletilla striata extract solution on zymosan-induced interstitial cystitis in rat.

AIMS: Interstitial cystitis (IC) is a chronic pain syndrome that is characterized by suprapubic pain upon bladder filling. Bletilla striata, a well-known traditional Chinese herb with established efficacy in wound healing and anti-inflammation, was hypothesized to improve the symptoms of IC possibly though forming a physical barrier that could isolate the bladder tissue from irritants. This study was conducted to evaluate the beneficial effects of intravesical treatment with B. striata extract solution (BSES) on visceral pain and bladder function of rats with zymosan-induced IC. METHODS: Thirty female rats were randomly divided into control group, zymosan-induced cystitis rats treated with normal saline (Z + NS), and zymosan-induced cystitis rats treated with BSES (Z + BSES). All rats underwent evaluation for abdominal withdrawal reflex (AWR) scores to assess visceral hypersensitivity, cystometrography, and electromyogram (EMG) of both external urethral sphincter and bladder detrusor. Data were analyzed by one way analysis of variance. RESULTS: The Z + NS group had an increased visceral hypersensitivity as compared to control group. Rats treated with BSES (Z + BSES group) had decreased AWR scores and amplitude of bladder detrusor-EMG. Besides, BSES treatment improved overactive bladder with significant effects on the extend of micturition interval and increase of storage of urine. CONCLUSIONS: Intravesical instillation of BSES can significantly alleviate zymosan-induced visceral hypersensitivity and bladder overactivity associated with IC. This study suggested that intravesical instillation with BSES might be a promising treatment for IC.

Possible role of intravenous administration of mesenchymal stem cells to alleviate interstitial cystitis/bladder pain syndrome in a Toll-like receptor-7 agonist-induced experimental animal model in rat.

BACKGROUND: Interstitial cystitis/bladder pain syndrome (IC/BPS) categorized with and without Hunner lesions is a condition that displays chronic pelvic pain related to the bladder with no efficacious treatment options. There are strong associations suggested between Hunner-type IC and autoimmune diseases. Recently, we established an animal model of Hunner-type IC using a Toll-like receptor-7 (TLR7) agonist. Intravenous infusion of mesenchymal stem cells (MSCs) can be used to treat injury via multimodal and orchestrated therapeutic mechanisms including anti-inflammatory effects. Here, we investigated whether infused MSCs elicit therapeutic efficacy associated with the TLR7-related anti-inflammatory pathway in our Hunner-type IC model. METHODS: Voiding behaviors were monitored 24 h prior to the Loxoribine (LX), which is a TLR7 agonist instillation in order to establish a Hunner-type IC model (from - 24 to 0 h) in female Sprague-Dawley rats. LX was instilled transurethrally into the bladder. At 0 h, the initial freezing behavior test confirmed that no freezing behavior was observed in any of the animals. The LX-instilled animals were randomized. Randomized LX-instilled rats were intravenously infused with MSCs or with vehicle through the right external jugular vein. Sampling tissue for green fluorescent protein (GFP)-positive MSCs were carried out at 48 h. Second voiding behavior tests were monitored from 72 to 96 h. After the final evaluation of the freezing behavior test at 96 h after LX instillation (72 h after MSC or vehicle infusion), histological evaluation with H&E staining and quantitative real-time polymerase chain reaction (RT-PCR) to analyze the mRNA expression levels of inflammatory cytokines were performed. RESULTS: Freezing behavior was reduced in the MSC group, and voiding behavior in the MSC group did not deteriorate. Hematoxylin-eosin staining showed that mucosal edema, leukocyte infiltration, and hemorrhage were suppressed in the MSC group. The relative expression of interferon-ß mRNA in the bladder of the MSC group was inhibited. Numerous GFP-positive MSCs were distributed mainly in the submucosal and mucosal layers of the inflammatory bladder wall. CONCLUSION: Intravenous infusion of MSCs may have therapeutic efficacy in a LX-instilled Hunner-type IC rat model via a TLR7-related anti-inflammatory pathway.

B6 Mouse Strain: The Best Fit for LPS-Induced Interstitial Cystitis Model.

Interstitial cystitis (IC) is a chronic inflammatory disease characterized by bladder pain and increased urinary frequency. Although the C57BL/6J (B6) and FVB/NJ (FVB) mouse strains are commonly used as animal models for studies involving the urinary system, few reports have compared their lower urinary tract anatomy, despite the importance of such data. Our study aimed to characterize bladder function changes in FVB and B6 mouse strains with lipopolysaccharide (LPS)-induced IC, to understand mouse model-based bladder research. The bladder function parameters were measured by cystometrogram. Histological assay was examined by hematoxylin and eosin stain, Masson's trichrome stain, and immunofluorescence staining. Results indicated that the two strains in the control group exhibited different bladder structures and functions, with significant anatomical differences, including a larger bladder size in the FVB than in the B6 strain. Furthermore, cystometry tests revealed differences in bladder function pressure. LPS-treated B6 mice presented significant changes in peak pressure, with decreased intercontraction intervals; these results were similar to symptoms of IC in humans. Each strain displayed distinct characteristics, emphasizing the care required in choosing the appropriate strain for bladder-model studies. The results suggested that the B6 mouse strain is more suitable for IC models.

Experimental Cannabinoid 2 Receptor Activation by Phyto-Derived and Synthetic Cannabinoid Ligands in LPS-Induced Interstitial Cystitis in Mice.

Interstitial cystitis (IC) is a chronic bladder disorder with unclear etiology. The endocannabinoid system has been identified as a key regulator of immune function, with experimental evidence for the involvement of cannabinoid receptors in bladder inflammation. This study used intravital microscopy (IVM) and behavioral testing in lipopolysaccharide-induced IC, to investigate the anti-inflammatory analgesic effects of a natural dietary sesquiterpenoid, beta-caryophyllene (BCP), which is present in cannabis among other plants, and has reported agonist actions at the cannabinoid 2 receptor (CB2R). BCP's anti-inflammatory actions were compared to the synthetic CB2R-selective cannabinoid, HU308, and to an FDA-approved clinical treatment (dimethyl sulfoxide: DMSO). IVM data revealed that intravesical instillation of BCP and/or HU308 significantly reduces the number of adhering leukocytes in submucosal bladder venules and improves bladder capillary perfusion. The effects of BCP were found to be comparable to that of the selective CB2R synthetic cannabinoid, HU308, and superior to intravesical DMSO treatment. Oral treatment with BCP was also able to reduce bladder inflammation and significantly reduced mechanical allodynia in experimental IC. Based on our findings, we believe that CB2R activation may represent a viable therapeutic target for IC, and that drugs that activate CB2R, such as the generally regarded as safe (GRAS) dietary sesquiterpenoid, BCP, may serve as an adjunct and/or alternative treatment option for alleviating symptoms of inflammation and pain in the management of IC.

Deletion or pharmacological blockade of TLR4 confers protection against cyclophosphamide-induced mouse cystitis.

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic inflammatory disease without consistently effective treatment. We investigate the role of toll-like receptor 4 (TLR4) on voiding dysfunction and inflammation in the cyclophosphamide (CYP)-induced mouse cystitis. Male C57BL/6 [wild-type, (WT)] and/or TLR4 knockout (TLR4-/-) mice were treated with an injection of CYP (300 mg/kg, 24 h) or saline (10 ml/kg). The pharmacological blockade of the TLR4 by resatorvid (10 mg/kg) was also performed 1 h prior CYP-injection in WT mice. Urodynamic profiles were assessed by voiding stain on filter paper and filling cystometry. Contractile responses to carbachol were measured in isolated bladders. In CYP-exposed WT mice, mRNA for TLR4, myeloid differentiation primary response 88, and TIR-domain-containing adapter-inducing interferon-ß increased by 45%, 72%, and 38%, respectively ( P < 0.05). In free-moving mice, CYP-exposed mice exhibited a higher number of urinary spots and smaller urinary volumes. Increases of micturition frequency and nonvoiding contractions, concomitant with decreases of intercontraction intervals and capacity, were observed in the filling cystometry of WT mice ( P < 0.05). Carbachol-induced bladder contractions were significantly reduced in the CYP group, which was paralleled by reduced mRNA for M2 and M3 muscarinic receptors. These functional and molecular alterations induced by CYP were prevented in TLR4-/- and resatorvid-treated mice. Additionally, the increased levels of inflammatory markers induced by CYP exposure, myeloperoxidase activity, interleukin-6, and tumor necrosis factor-alpha were significantly reduced by resatorvid treatment. Our findings reveal a central role for the TLR4 signaling pathway in initiating CYP-induced bladder dysfunction and inflammation and thus emphasize that TLR4 receptor blockade may have clinical value for IC/BPS treatment.

Bladder wall injection of mesenchymal stem cells ameliorates bladder inflammation, overactivity, and nociception in a chemically induced interstitial cystitis-like rat model.

INTRODUCTION AND HYPOTHESIS: We investigated the effects of bladder wall injection of mesenchymal stem cells (MSCs) on bladder tissues, function, and nociceptive behavior in a chemically induced interstitial cystitis-like rat model. METHODS: Chemical cystitis of female rats was induced by intravesical instillation of 0.1 N hydrochloride (HCl) once a week for 2 weeks. Bladders were harvested 1, 2, 3, and 4 weeks after the second application for histological examination. Adipose-derived MSCs (HCl + MSCs) or phosphate-buffered saline (HCl + PBS) was injected into the bladder wall at the time of the second application of HCl. Histological examination, nociceptive behavior, and cystometrograms were evaluated 2 weeks after the injection compared with controls, which received instillation and injection of PBS into the bladder (sham + PBS). RESULTS: The number of mast cells and expression of tumor necrosis factor-α (TNF-α) and transforming growth factor-ß (TGF-ß) were significantly increased at 1 and 2 weeks, and expression of collagen fibers was significantly increased from 2-4 weeks after the second application of HCl. Significantly increased nociceptive behavior, number of mast cells, expression of TNF-α, TGF-ß, and collagen fibers were observed in HCl + PBS compared with sham + PBS, whereas these changes were significantly decreased in HCl + MSCs compared with HCl + PBS. In addition, bladder capacity and voiding threshold pressures were significantly decreased in HCl + PBS but not in HCl + MSCs compared with sham + PBS. CONCLUSIONS: The results suggest that bladder injection of MSCs ameliorates inflammation and fibrosis in bladder tissues, bladder overactivity, and nociception in a rat model of chemically induced cystitis.

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

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.

Effects of hyperbaric oxygen therapy on hydrochloric acid-induced interstitial cystitis in rats: a histological and ultrastructural study.

INTRODUCTION: Currently no definitive cure exists for interstitial cystitis (IC). We investigated the therapeutic effects of hyperbaric oxygen (HBO2) therapy in this syndrome in an experimental IC model through biochemical analyses and histopathological assessments. METHODS: 24 Sprague Dawley rats were divided into three treatment groups sham (transurethral intravesical injection with sterile distilled water), rats with IC (induced by transurethral intravesical injection with hydrochloric acid), and rats with IC + HBO2. After completion of experiments the animals were sacrificed and their urinary bladders were removed surgically. Tissues were evaluated by light and electron microscopy. Lesion index scoring system for IC was used to evaluate vesical injury. TNF-α levels were measured by ELISA test kit. RESULTS: Lesion index scores and TNF-α levels of the sham and IC + HBO2 treatment groups were quite similar (p < 0.01). Although HBO2 treatment did not show any effect in reducing the number of mast cells (p > 0.05), it reduced the mast cell activity (p < 0.05). All parameters except mitochondrial damage (p > 0.05) were improved in the IC + HBO2 treatment group compared to the IC without HBO2 treatment group. CONCLUSION: HBO2 treatment may alleviate the inflammation, may lead to a certain degree of reversal of adverse histopathological changes, and is effective in enhancing the healing process in interstitial cystitis. We believe that HBO2 treatment may be included as a weapon in our armamentarium against IC.

Polaprezinc attenuates cyclophosphamide-induced cystitis and related bladder pain in mice.

Cav3.2 T-type Ca(2+) channels targeted by H2S, a gasotransmitter, participate in cyclophosphamide-induced cystitis and bladder pain. Given that zinc selectively inhibits Cav3.2 among T-channel isoforms and also exhibits antioxidant activity, we examined whether polaprezinc (zinc-l-carnosine), a medicine for peptic ulcer treatment and zinc supplementation, reveals preventive or therapeutic effects on bladder inflammation and/or pain in the mouse with cyclophosphamide-induced cystitis, a model for interstitial cystitis. Systemic administration of cyclophosphamide caused cystitis-related symptoms including increased bladder weight and vascular permeability, and histological signs of bladder edema, accompanied by bladder pain-like nociceptive behavior/referred hyperalgesia. All these symptoms were significantly attenuated by oral preadministration of polaprezinc at 400 mg/kg. The same dose of polaprezinc also prevented the increased malondialdehyde level, an indicator of lipid peroxidation, and protein upregulation of cystathionine-γ-lyase, an H2S-generating enzyme, but not occludin, a tight junction-related membrane protein, in the bladder tissue of cyclophosphamide-treated mice. Oral posttreatment with polaprezinc at 30-100 mg/kg reversed the nociceptive behavior/referred hyperalgesia in a dose-dependent manner without affecting the increased bladder weight. Together, our data show that zinc supplementation with polaprezinc prevents the cyclophosphamide-induced cystitis probably through the antioxidant activity, and, like T-channel blockers, reverses the established cystitis-related bladder pain in mice, suggesting novel therapeutic usefulness of polaprezinc.

Statin Use Is Associated with Bladder Pain Syndrome/Interstitial Cystitis: A Population-Based Case-Control Study.

INTRODUCTION: Statin may induce epithelial dysfunction of the bladder urothelium. Epithelial dysfunction was proposed as one of the major potential etiologies for bladder pain syndrome/interstitial cystitis (BPS/IC). In this study, we examined the association between statin use and BPS/IC using a population-based study. SUBJECTS AND METHODS: This case-control study used the Taiwan Longitudinal Health Insurance Database. In total, 815 female subjects with BPS/IC and 4075 randomly selected female controls were included. We used a conditional logistic regression to compute the odds ratio (OR) for having previously used statins between cases and controls. RESULTS: A conditional logistic regression analysis showed that the OR of prior statin users for cases was 1.52 (95% confidence interval (CI): 1.19-1.94) compared to controls after adjusting for diabetes, hypertension, coronary heart disease, obesity, chronic pelvic pain, irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, depression, panic disorder, migraines, sicca syndrome, allergies, endometriosis, and asthma. Furthermore, adjusted ORs of regular and irregular statin use for cases were 1.58 (95% CI: 1.20-2.08) and 1.53 (95% CI: 1.02-2.31), respectively, compared to controls. CONCLUSION: We concluded that there was an association between statin use and BPS/IC.