Cystitis In Rats Research Articles

Production of GcMAF with Anti-Inflammatory Properties and Its Effect on Models of Induced Arthritis in Mice and Cystitis in Rats.

Vitamin D3 transporter (DBP) is a multifunctional protein. Site-specific deglycosylation results in its conversion to group-specific component protein-derived macrophage activating factor (GcMAF), which is capable of activating macrophages. It has been shown that depending on precursor conversion conditions, the resulting GcMAF activates mouse peritoneal macrophages towards synthesis of either pro- (IL-1β, TNF-α-M1 phenotype) or anti-inflammatory (TGF-β, IL-10-M2 phenotype) cytokines. The condition for the transition of the direction of the inflammatory response of macrophages when exposed to GcMAF is the initial glycosylated state of the population of DBP molecules and the associated effective deglycosylation of DBP by β-galactosidase. In vivo experiments with GcMAF exhibiting anti-inflammatory properties on models of induced arthritis in mice and cystitis in rats indicate a significant anti-inflammatory effect of the macrophage activator. The feasibility of unidirectional induction of anti-inflammatory properties of macrophages allows creation of combined therapeutic platforms where M2 macrophages are among the key therapeutic components.

The serotonin(5-HT)2A receptor is involved in the hypersensitivity of bladder afferent neurons in cyclophosphamide-induced cystitis

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic bladder inflammation characterized by the main symptoms of urinary frequency, urgency, and pelvic pain. The hypersensitivity of bladder afferent neurons is considered a significant pathophysiologic mechanism in IC/PBS. Serotonin (5-HT, 5-hydroxytryptamine) receptors are known to be involved in the regulation of the micturition reflex and hyperalgesia, but the effect of 5-HT receptors on cystitis remains unknown. In this study, a rat model of interstitial cystitis induced by intraperitoneal injection of cyclophosphamide (CYP) was used to investigate the role of 5-HT receptors on cystitis. The histology and urodynamics exhibited chronic cystitis and overactive bladder in CYP-treated rats. Notably, among 5-HT1A, 5-HT2A and 5-HT7 receptors, the expression of 5-HT2A receptor was significantly increased in bladder afferent neurons in CYP-treated rats. Intrathecal administration of the 5-HT2A receptor antagonist M100907 could alleviate bladder overactivity and hyperalgesia in CYP-induced cystitis rats. Neuronal calcium imaging of bladder afferent neurons revealed increased calcium influx induced by the 5-HT2A receptor agonist or capsaicin in cystitis rats, which could be inhibited by M100907. Moreover, RNA sequencing indicated that differentially expressed genes were enriched in inflammation-related pathways and cellular calcium homeostasis. These findings suggest that the 5-HT2A receptor is involved in the hypersensitivity of bladder afferent neurons in CYP-induced cystitis, and M100907 could alleviate bladder overactivity and hyperalgesia in CYP-induced cystitis by inhibiting neuronal hypersensitivity in the afferent pathways. The 5-HT2A receptor may be a potential therapeutic target for the treatment of IC/BPS.

Elucidation of the pathophysiology of interstitial cystitis/bladder pain syndrome via experimental autoimmune cystitis rat model.

Although the cause of interstitial cystitis/painful bladder syndrome (IC/PBS) remains unknown, autoimmune involvement has been strongly suggested to be a contributing factor. To elucidate the pathophysiology of IC/PBS, we characterized the experimental autoimmune cystitis (EAC) in rats. Adult female Sprague-Dawley rats were divided into the EAC and control groups. The EAC rats were generated by administrating a homogenate of donor rat bladder tissue as a bladder antigen. The characteristics of the two groups were determined by evaluating pain behavior and conducting cystometry, histopathology, and molecular analyses. The EAC rats showed: 1) a decreased paw withdrawal threshold, 2) a reduced intercontraction interval on cystometry, 3) the irregular surfaces of the umbrella cells of epithelium throughout the bladder wall, 4) accumulation of stress granules in the bladder and vascular endothelium, 5)the increased expression of genes related to inflammation and ischemia at the mRNA and protein levels, 6) a significantly increased paw withdrawal threshold with pain treatment, and 7) the induction of glomerulation of the bladder wall, epithelium denudation, and lymphocyte infiltration in the interstitium by bladder distension. These results suggest that the EAC rats showed pain and frequent urination with the overexpression of inflammatory chemokines, reflecting clinical IC/BPS, and the bladder epithelium and vascular endothelium may be the primary sites of IC/BPS, and bladder injury, such as bladder distension, can cause progression from BPS to IC with Hunner lesions.NEW & NOTEWORTHY The experimental autoimmune cystitis model rats showed pain and frequent urination with the overexpression of inflammatory chemokines, reflecting clinical interstitial cystitis/painful bladder syndrome (IC/PBS), and the bladder epithelium and vascular endothelium may be the primary sites of IC/BPS, and bladder injury, such as bladder distension, can cause progression from BPS to IC with Hunner lesions.

Antibacterial and therapeutic effects of low energy shock waves on uropathogenic E. coli investigated by in vitro and in vivo cystitis rat model.

Low-energy shock waves (LESWs) are known to alter cell-membrane permeability. This study aimed to investigate the effect of LESWs on Escherichia coli and E. coli-induced cystitis in rats. Standardized suspensions of E. coli ATCC25922 were treated with or without LESWs (100 or 300 pulses; 0.12mJ/mm2; 2pulses/s) followed by bacterial counting, an antibiotic sensitivity test, and gene ontology analysis and gene-set enrichment analysis. Intravesical administration of saline or E. coli (0.5mL with 108CFU/mL) for 30min was performed in female Sprague-Dawley rats. The rats were treated with or without LESWs (300 pulses; 0.12mJ/mm2; 2pulses/s) on days 4 and 5. The changes in inflammatory reactions, uroplakin IIIa staining, and correlation with urodynamic findings were assessed on day 8. LESW treatment induced a decrease in CFU and the autoaggregation rate and increased the inhibition zone sizes in a cefazolin-sensitivity study. These changes were associated with gene expression in regulation of cellular membrane components, biofilm formation, and the ATP-binding cassette transporter pathway. E. coli induced bladder hyperactivity and an inflammatory reaction as well as decreased uroplakin IIIa staining; these effects were partially reversed by LESW treatment. The LESW antibacterial effect occurs by altering bacterial cell-membrane gene expression, enhancing antibiotic sensitivity, and inhibiting bladder inflammatory reaction and overactivity. These findings support the potential benefits of LESWs for treatment of recurrent or refractory bacterial cystitis.

Histological Study on the Possible Protective Effect of Pumpkin Seed Oil on Cyclophosphamide Induced Hemorrhagic Cystitis in Adult Male Albino Rat

Histological Study on the Possible Protective Effect of Pumpkin Seed Oil on Cyclophosphamide Induced Hemorrhagic Cystitis in Adult Male Albino Rat

Stem cell therapy for interstitial cystitis/bladder pain syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease with limited treatment options. Current multidisciplinary approach targeting bladder inflammation and urothelial dysfunction has limited durable effect that major surgery is ultimately required for both Hunner and non-Hunner type IC. Various investigational attempts are underway to avoid such operations and preserve the urinary bladder. Stem cell therapy is a fascinating option for treating chronic illnesses. Stem cells can self-renew, restore damaged tissue, and have paracrine effects. The therapeutic efficacy and safety of stem cell therapy have been demonstrated in numerous preclinical models, primarily chemically induced cystitis rat models. Only one clinical trial (phase 1 study) has investigated the safety of human embryonic stem cell-derived mesenchymal stem cells in three Hunner-type IC patients. Under general anesthesia, participants underwent cystoscopic submucosal stem cell injection (2.0 × 107 stem cells/5 mL). No safety issues were reported up to 12 months of follow-up and long-term follow-up (up to 3 years). Although there were variations in therapeutic response, all patients reported significant improvement in pain at 1 month postoperatively. One patient underwent fulguration of the Hunner lesion after the trial, but others reported an overall improvement in pain. The analysis on phase 1/2a trial which had several modifications in protocol is currently ongoing. Despite several limitations that need to be overcome, stem cell therapy could be a potential therapeutic option for treating IC/BPS. Clinical outcome on phase 1/2a trial is important and might provide more insight into the clinical application of stem cell therapy for IC/BPS.

Brainstem nuclei responsive to cystometry in both endometriosis and cystitis rat models: C-fos immunohistochemistry study.

Although the co-occurrence of interstitial cystitis (IC) and endometriosis (ENDO) is remarkably high, the exact pathophysiology for this co-occurrence is unknown. The convergence of the inputs from the involved structures to the same neuronal centers may suggest neuronal hyperexcitability as a mechanism for this co-occurrence. The present study aimed to investigate the association between IC and ENDO, by studying the changes in brainstem responses to cystometry in a rat model of ENDO and cyclophosphamide (CYP)-induced IC using c-fos immunohistochemistry. Following cystometry the brainstem areas that had significant increase in c-fos expression in ENDO alone included: periaqueductal gray (PAG) nuclei, dorsal raphe nucleus, raphe obscurus nucleus, kolliker- Fuse areas, and area postrema. However, the brainstem areas that had increased significantly in the c-fos expression in the ENDO and CYP treated animals included: gigantocellular nucleus, lateral paragigantocellular nucleus, caudoventrolateral nucleus, rostroventrolateral/caudoventrolateral nucleus, lateral reticular nucleus, locus coeruleus, lateral PAG, raphe pallidus nucleus, raphe magnus nucleus, rostroventrolateral nucleus, dorsal motor nucleus of vagus, and solitary tract nucleus. Whereas only lateral parabrachial nucleus showed significant increase in c-fos expression in CYP treated animals alone. The results of the present study demonstrate the overlap of brainstem nuclei that are excited by urinary bladder under ENDO and IC conditions. The pattern of hyperexcitability of the brainstem nuclei may help in understating the pathophysiology of IC and ENDO conditions.

Effect of photobiomodulation on lower urinary tract dysfunction in rat cystitis model.

Photobiomodulation selectively controls the activity of the sensory nervous system associated with A-delta and C fibers. Hypersensitivity involving the afferent A-delta and C fibers occurs in cystitis and decreases urinary function. This study aimed to investigate the effect of photobiomodulation on urinary storage dysfunction and voiding functions in cystitis model rats. We prepared the rat cystitis model. Under anesthesia, a cannula was connected to the bladder via a ventral incision. 0.3% acetic acid or saline was injected into the bladder. Continuous cystometry was performed, measuring bladder pressure and voiding urine volume with rats freely mobile. Laser irradiation was applied to the L6 lumbosacral intervertebral foramen using an 830 nm laser. Residual urine was extracted post-cystometry. In the rat cystitis model groups, there was a significant decrease in the voiding interval and volume compared to the group receiving normal saline infusion. After sham or laser irradiation, only the group with laser irradiation showed a significant increase in voiding interval (217%, p = 0.0002) and voiding volume (192%, p = 0.0012) in the parameters of storage dysfunction. The basal pressure, intravesical pressure, and residual urine volume remained unchanged in all groups before and after irradiation. This study indicates that photobiomodulation may improve urine storage dysfunction without exacerbating voiding function in a rat model of cystitis. Thus, photobiomodulation may be a new treatment option for the hypersensitivity and detrusor overactivity caused by cystitis.

Umbilical Cord Mesenchymal Stem Cells Overexpressing Heme Oxygenase-1 Promotes Symptoms Recovery in Cystitis Rats by Alleviating Neuroinflammation.

Interstitial cystitis/bladder pain syndrome (IC/BPS) seriously reduces the patient's quality of life, yet current therapies only provide partial relief. In the spinal dorsal horn (SDH), neuroinflammation plays a pivotal role in the development of IC. Injection of human umbilical cord mesenchymal stem cells (hUMSCs) to reduce inflammation is an effective strategy, and heme oxygenase-1 (HO-1) exhibits anti-nociceptive effect in neuroinflammatory pain. This study aimed to test the therapeutic effects of hUMSCs overexpressing HO-1 on cyclophosphamide-induced cystitis rat model. Cystitis rats were transplanted with altered cells and then assessed for 3 weeks. A series of behavioral measurements would be trial including suprapubic mechanical allodynia, depressive-like behaviors, micturition frequency, and short-term memory function. Additionally, western blot, immunofluorescence staining, and ELISA kit test for anti-inflammation effect. HUMSCs were capable of being transduced to overexpress HO-1. Injection of hUMSCs overexpressing HO-1 was more effective than hUMSCs alone in alleviating behavioral symptoms in rats. Furthermore, hUMSCs overexpressing HO-1 inhibited the activation of glial and TLR4/p65/NLRP3 pathway, decreased the levels of pro-inflammatory cytokines in the SDH region. Surprisingly, it markedly increased anti-inflammatory cytokine IL-10, reduced MDA content, and protected GSH concentrations in local environment. Our results suggest that injecting hUMSCs overexpressing HO-1 intrathecally can significantly promote functional outcomes in cystitis rats by reducing neuroinflammation, at least, partly through downregulating TLR4/p65/NLRP3 signaling pathway in the SDH region. This cell therapy affords a new strategy for IC/BPS treatment.

Effects of low-intensity extracorporeal shock wave therapy on lipopolysaccharide cystitis in a rat model of interstitial cystitis/bladder pain syndrome.

To investigate the effect of low-intensity extracorporeal shock wave therapy (LiESWT) on lipopolysaccharide (LPS)-induced cystitis in an animal model of interstitial cystitis/bladder pain syndrome (IC/BPS). Sprague-Dawley rats were divided into three groups: control, cystitis (LPS group, intravesical injection of LPS (1mg) twice), and cystitis with LiESWT (LiESWT group). On the third and fourth days, LiESWT was administered (0.12mJ/mm2, 300 shots each time) on the lower abdomen toward the bladder. On the seventh day, the rats underwent pain assessment and a metabolic cage study. Subsequently, a continuous cystometrogram (CMG) was performed under urethane anaesthesia. Immunohistochemical studies were also performed, including S-100 staining, an immunohistochemical marker of Schwann cells in the bladder. In the LPS group, the pain threshold in the lower abdomen was significantly lower than that in the control group. In the metabolic cage study, the mean voided volume in the LPS group significantly increased. The CMG also revealed a significant decrease in bladder contraction amplitude, compatible with detrusor underactivity in the LPS group. Immunohistochemical studies showed inflammatory changes in the submucosa, increased fibrosis, and decreased S-100 stain-positive areas in the muscle layer of the LPS group. In the LiESWT group, tactile allodynia and bladder function were ameliorated, and S-100 stain-positive areas were increased. By restoring nerve damage, LiESWT improved lower abdominal pain sensitivity and bladder function in an LPS-induced cystitis rat model. This study suggests that LiESWT may be a new therapeutic modality for IC/BPS.

Potential Protective Effects of Mesna and Vitamin D Separately or Concomitantly on Cyclophosphamide Induced Hemorrhagic Cystitis in Rats

Potential Protective Effects of Mesna and Vitamin D Separately or Concomitantly on Cyclophosphamide Induced Hemorrhagic Cystitis in Rats

4-PBA inhibits endoplasmic reticulum stress to improve autophagic flux in the treatment of protamine/lipopolysaccharide-induced interstitial cystitis in rats

Interstitial cystitis (IC) has severe clinical symptoms with unclear mechanism. The continuous inflammatory response of the bladder is the basis of its pathogenesis. Endoplasmic reticulum stress (ERS) is involved in the regulation and development of various inflammatory diseases. And autophagy plays an important role in IC. In this study, we mainly focus on the therapeutic effect of endoplasmic reticulum stress and autophagy on protamine/lipopolysaccharide-induced interstitial cystitis. Female Sprague–Dawley rats were randomized into three experimental groups as follows: sham controls(N), IC alone, and IC+4-PBA.Rats in group IC received 10 mg/ml PS in the urinary bladder, followed by 2 mg/ml LPS instillation after 30 min, IC+4-PBA group SD rats received 4-PBA solution administered intragastrically once a day for 5 days. ERS biomarker (GRP78), autophagy-related proteins (LC3I/II, and Beclin1), autophagic flux biomarker (P62), inflammatory biomarkers (IL-6, TNF-a, NF-κB), apoptotic biomarkers (Caspase 3, Bax) were highest in the IC group compared to IC+4-PBA group and N group and the biomarkers expression in IC+4-PBA group were lower than in the IC group, anti-apoptotic biomarker (Bcl-2) was highest in the N group compared to the IC group and IC+4-PBA group and lower in the IC group than in the IC+4-PBA group, oxidative stress biomarkers (HO-1, NQO-1) were remarkably lower in the control group than in the IC and IC+4-PBA groups and notably lower in the IC group than in the IC+4-PBA group. The histological score and mast cell count demonstrated most severe in the IC group than those in the IC+4-PBA group. TUNEL assay examined the level of apoptosis in IC group was higher than in the IC+4-PBA group. The bladder micturition function was significantly improved with 4-PBA treatment. 4-PBA inhibits ERS to recover autophagic flux, and then to suppress the bladder oxidative stress, the inflammatory reaction and apoptosis, finally improve the bladder urinary function in Protamine/Lipopolysaccharide (PS/LPS) induced IC.

Intrathecal umbilical cord mesenchymal stem cells injection alleviates neuroinflammation and oxidative stress in the cyclophosphamide-induced interstitial cystitis rats through the Sirt1/Nrf2/HO-1 pathway

AimsNeuroinflammation in the spinal dorsal horn (SDH) region plays an important role in the pathogenesis of interstitial cystitis (IC)/bladder pain syndrome (BPS). Oxidative stress is an important etiological factor for inflammatory diseases. This study aimed to investigate the therapeutic effects of umbilical cord mesenchymal stem cells UMSCs on neuroinflammation and oxidative stress in IC and the underlying mechanisms. Materials and methodsRats were intraperitoneally injected with cyclophosphamide (50 mg/kg bodyweight) to establish the IC animal model. Additionally, rats were intrathecally injected with a Sirt1-specific agonist (SRT1720; 8 μg/rat) or inhibitor (EX527; 8 μg/rat). Furthermore, rats were intrathecally injected with human UMSCs (hUMSCS; 8 × 105 cells/rat). Rat behavior was examined using the mechanical allodynia test, novel object recognition test, sucrose preference test, and urodynamics analysis. Neuroinflammation and oxidative stress the SDH region were examined using western blotting, immunofluorescence, enzyme-linked immunosorbent assay, and commercial kits. Key findingsThe Sirt1/Nrf2/HO-1 pathway was downregulated in IC rats. Sirt1 activation and inhibition differentially affected the behavior of IC rats. hUMSCs effectively mitigated the upregulation of oxidative stress, proinflammatory cytokines, and glial activation in the SDH region. Additionally, hUMSCs suppressed mechanical allodynia, dysregulated urodynamics, memory deficits, and depressive-like behavior in IC rats. hUMSCs exerted therapeutic effects through the Sirt1/Nrf2/HO-1 pathway. Significanceintrathecal hUMSCs injection alleviated behavioral deficits of IC rats by mitigating neuroinflammation and oxidative stress through the Sirt1/Nrf2/HO-1 pathway and can be potentially an effective therapeutic strategy for IC.

Protective potential of pterostilbene against cyclophosphamide-induced nephrotoxicity and cystitis in rats.

Cyclophosphamide (CYP) is an antitumor drug. However, in addition to its antitumor affect, CYP can also lead to nephrotoxicity and hemorrhagic cystitis. The purpose of this study was to investigate the potential protective effects of Pterostilbene (Pte), a natural antioxidant as a resveratrol analog against CYP-induced nephrotoxicity and cystitis in rats. Twenty-one male Sprague Dawley rats were divided into 3 equal groups. The control group and the CYP group (CYPG) received 1ml/kg sunflower oil per day, and the CYP + Pte group (CYP + PteG) 40mg/kg per day Pte dissolved in sunflower oil once a day via the oral route for 14days. In addition, on day 9 of the experiment, CYPG and CYP + PteG received a single dose of 200mg/kg CYP dissolved in saline solution, while the control group received a single dose of 10ml/kg saline solution, via the intraperitoneal route. Bladder and kidney tissues were collected for histological and biochemical evaluations. Pte was observed to reduce CYP-derived increases in malondialdehyde level, total oxidant status (TOS), the oxidative stress index (OSI), and apoptosis in kidney tissues and to cause an increase in superoxide dismutase levels. It also reduced CYP-derived increases in TOS, OSI, and apoptosis in bladder tissue. Moreover, Pte also ameliorated histopathological findings associated with CYP-induced tissue damage in both the kidney and bladder. Our study findings show that Pte may exhibit a protective effect against CYP-induced nephrotoxicity and cystitis.

Rosmarinic acid ameliorates HCl-induced cystitis in rats.

Shiso (Perilla frutescens var crispa f. purprea) is a traditional medicinal herb that exerts anti-inflammatory effects and alleviates lower urinary tract symptoms. In this study, we examined the effects of rosmarinic acid, a major polyphenol in shiso, on urinary function and the bladder in a rat hydrochloric acid-induced cystitis model. Sprague-Dawley rats were administered intravesically with hydrochloric acid or saline solution (control) to induce cystitis. Afterwards, the rats were administered orally with distilled water or rosmarinic acid for three days and then the intravesical pressure was measured, a stretch stimulation test was performed using the harvested bladder, and histological and biochemical analyses were performed. In addition, we investigated the effects of rosmarinic acid on the expression of inflammation-related molecules in normal human bladder epithelial cells. Rosmarinic acid ameliorated hydrochloric acid-induced shortening of micturition interval by 49%. In hydrochloric acid-treated bladders, significantly more prostaglandin E2 was released after stretching; however, rosmarinic acid suppressed its release to control levels. Rosmarinic acid also reduced hydrochloric acid-induced epithelial thickening and the levels of inflammatory molecules in the bladder. Furthermore, rosmarinic acid suppressed interleukin 1β-induced increases in Cox2 and Il6 expression in bladder epithelial cells. These findings indicate that rosmarinic acid can ameliorate hydrochloric acid-induced cystitis in rats and that these effects are due, at least in part, to its anti-inflammatory effects on the bladder and inhibition of stretch-induced prostaglandin E2 release.

Protective effects of ursolic acid on cyclophosphamide induced hemorrhagic cystitis in rats

Cyclophosphamide (CP) is a commonly used antineoplastic agent despite its adverse effects. Hemorrhagic cystitis (HC)is one of the most common side effects of CP. Although Mesna is commonly used to prevent HC, it suffers from few sideeffects. Therefore, search for better alternate substance still continues. In this study, we studied the effects of ursolic acid(UA), one of the active ingredients of Plantago major, commonly called plantain or white man’s foot, in CP-inducedhemorrhagic cystitis in rats. Forty-nine Sprague−Dawley rats in seven equal groups viz. control (C); cyclophosphamide(CP); cyclophosphamide+Mesna (CPMesna); cyclophosphamide+ursolic acid [100 (CPUA100) and 200 mg (CPUA200)],and cyclophosphamide+ mesna+ ursolic acid (100, (CPMesnaUA100) and (200 mg (CPMesnaUA200) were investigated forinducible nitric oxide synthetase (iNOs), total antioxidant status (TAS), total antioxidant status (TOS), TNF–α, interleukin10 (IL–10) and interleukin 6 (IL–6) levels from blood samples. The data obtained were statistically analyzed using SPSSand both Kruskall Wallis and Dunn tests were performed. Value of P <0.05 was considered as statistically significant. Ourresults have revealed that the UA applied groups better preserve compared to CP group. However, it was observed that thisprotection is comparatively weaker than the Mesna and UA-Mesna combinations. Hence, it is suggested that the urosilicacid could prevent cyclophosphamide induced hemorrhagic cystitis, and also extends support to Mesna applications.Overall, it has been observed that ursolic acid has limited protective effects against CP-induced hemorrhagic cystitis, andcan serve as a supportive agent in inhibiting hemorrhagic cystitis.

Uro-protective role of chrysin against cyclophosphamide-induced hemorrhagic cystitis in rats involving the turning-off NF-κB/P38-MAPK, NO/PARP-1 and STAT-3 signaling cascades

BackgroundChemotherapeutic agents are used to treat a wide range of cancer types, but they cause serious side effects which must be managed after treatment. Cyclophosphamide (CYP) is one of chemotherapeutic drugs that causes hemorrhagic cystitis (HC) induced by acrolein. ObjectiveThe current investigation intended to uncover the role of chrysin (CHR) in CYP-induced HC in rats and explore the signaling pathway beyond this effect. Analysisprocess: A single dose of CYP (200 mg/kg/IP) was injected, meanwhile CHR (25, 50 and 100 mg/kg, P.O) was administered respectively for 7 days prior to CYP administration and resume for 7 days afterwards. Urinary bladder tissue was then isolated from all rats to assess oxidative stress and inflammatory biomarkers. Moreover, histopathological examinations were performed. ResultsTreatment with CHR showed a marked alleviation in oxidative stress biomarkers induced by CYP. Furthermore, CHR treatment presented a dose-dependent boost in the anti-inflammatory; IL-10 levels and a drop in the pro-inflammatory biomarkers; IL-1β, IL-6, and TNF–α. Additionally, stabilization of the PARP-1 protein expression was also detected thus preventing DNA damage. Similarly, CHR restored the urinary bladder cGMP levels. Notably, CHR treatment was accompanied with inhibition in NF-κB/p38-MAPK, NO/PARP-1 and STAT-3 signaling pathways inflammatory cascades. All these findings conformed with the histopathological examinations as well as iNOS immunostaining in the urinary bladder tissue. ConclusionCo-administration of CHR and CYP attained uro-protective therapeutic potential to guard against HC as well as spot the tangled mechanism of CHR in attenuating the HC induced by CYP.

Piezo2 Channel Upregulation is Involved in Mechanical Allodynia in CYP-Induced Cystitis Rats

Mechanical sensing Piezo2 channel in primary sensory neurons has been shown contribute to mechanical allodynia in somatic chronic pain conditions. Interstitial cystitis (IC)-associated pain is often triggered by bladder filling, a presentation that mimics the mechanical allodynia. In the present study, we aimed to examine the involvement of sensory Piezo2 channel in IC-associated mechanical allodynia using a commonly employed cyclophosphamide (CYP)-induced IC model rat. Piezo2 channels in dorsal root ganglia (DRGs) was knocked down by intrathecal injections of Piezo2 anti-sense oligodeoxynucleotides (ODNs) in CYP-induced cystitis rats, and mechanical stimulation–evoked referred bladder pain was measured in the lower abdomen overlying the bladder using von Frey filaments. Piezo2 expression at the mRNA, protein, and functional levels in DRG neurons innervating the bladder was detected by RNA-fluorescence in situ hybridization, western blotting, immunofluorescence, and Ca2+ imaging, respectively. We found that Piezo2 channels were expressed on most (> 90%) of the bladder primary afferents, including afferents that express CGRP, TRPV1 and stained with isolectin B4. CYP-induced cystitis was associated with Piezo2 upregulation in bladder afferent neurons at the mRNA, protein, and functional levels. Knockdown of Piezo2 expression in DRG neurons significantly suppressed mechanical stimulation–evoked referred bladder pain as well as bladder hyperactivity in CYP rats compared to CYP rats treated with mismatched ODNs. Our results suggest upregulation of Piezo2 channels is involved in the development of bladder mechanical allodynia and bladder hyperactivity in CYP-induced cystitis. Targeting Piezo2 might be an attractive therapeutic approach for IC-related bladder pain.

Therapeutic effects of axitinib, an anti-angiogenic tyrosine kinase inhibitor, on interstitial cystitis

To investigate the therapeutic effects of axitinib, a tyrosine kinase inhibitor, in an interstitial cystitis (IC) rat model. IC patients with or without Hunner lesion and non-IC controls were enrolled (n = 5/group). Bladder tissues were stained with vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR-2), platelet-derived growth factor (PDGF), and PDGF receptor B (PDGFR-B). The IC group showed extensive VEGFR-2 and PDGFR-B staining compared with controls. Next, ten-week-old female Sprague Dawley rats were divided into three groups (n = 10/group): sham, hydrochloride (HCl), and axitinib groups. One week after HCl instillation (day 0), the axitinib group received oral axitinib (1 mg/kg) for five consecutive days and pain was evaluated daily. Bladder function, histology and genetics were evaluated on day 7. The pain threshold significantly improved 3 days after axitinib administration. Axitinib decreased non-voiding contraction and increased the micturition interval and micturition volume and alleviated urothelial denudation, angiogenesis, mast cell infiltration, and fibrosis. HCl instillation increased the expression of tyrosine kinase receptors, including VEGFR-2 and PDGFR-B; axitinib administration inhibited their expression. Oral administration of axitinib improved pain, voiding profiles, and urothelial integrity by inhibiting angiogenesis in IC rat model. Axitinib may have potential therapeutic efficacy in IC patients.

PD05-09 EFFECTS OF SUNOBINOP (V117957) IN A MODEL OF ACUTE CYSTITIS INDUCED BY CYCLOPHOSPHAMIDE

You have accessJournal of UrologyCME1 Apr 2023PD05-09 EFFECTS OF SUNOBINOP (V117957) IN A MODEL OF ACUTE CYSTITIS INDUCED BY CYCLOPHOSPHAMIDE Garth Whiteside, Stamford, CT, Celine Auge, and Philippe Lluel Garth WhitesideGarth Whiteside More articles by this author , Stamford Stamford More articles by this author , CT CT More articles by this author , Celine AugeCeline Auge More articles by this author , and Philippe LluelPhilippe Lluel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003229.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Interstitial Cystitis (IC) is a chronic urological disorder characterized by pain urinary urgency, frequency and nocturia. Not all patients are responsive to existing treatments which are also limited by side-effects. As such new treatments with novel mechanisms of action are needed. Sunobinop (V117957) is a selective partial agonist of the nociceptin/orphanin-FQ (N/OFQ) peptide receptor which is excreted unchanged by the kidneys. The objective of these studies was to examine the effect of sunobinop on visceral pain in a model of interstitial cystitis in female rats. METHODS: Female Sprague-Dawley rats (10/group) were administered sunobinop (30 mg/kg, p.o.), ibuprofen (300 mg/kg, p.o.) or vehicle and 5 minutes later a single dose of cyclophosphamide (CYP; 150 mg/kg i.p). Tactile sensitivity (von Frey fibers) was measured at baseline, 2, 3, 4 and 24 hr after CYP. Parameters analyzed were nociceptive threshold (g), nociceptive scores (%) and area under the nociception curve (AUC) across two fiber ranges (1-6 g and 6-26 g) all of which were expressed as mean±standard error of the mean (SEM) with significance set at p≤0.05. RESULTS: At all evaluated time points CYP induced a significant decrease of nociception measures as compared to saline (p<0.0001) indicating successful model development. Ibuprofen-treated rats displayed a significant overall increase in nociceptive thresholds and significantly decreased nociceptive scores and AUC measures as compared to vehicle (p<0.0001). Post hoc statistical analysis showed a slight and gradual decrease of ibuprofen effect was observed over time. Sunobinop produced an overall inhibitory effect on nociceptive thresholds (significant at 3 hr), a significant decrease in nociceptive scores and a significant decrease in AUCs starting from 2h and up to 24h after CYP injection (p<0.01). After 3h, efficacy of sunobinop decreased slightly and gradually over time. CONCLUSIONS: The positive control, ibuprofen, significantly decreased pain responses, as compared to vehicle in an acute model of CYP induced IC. Likewise, sunobinop was significantly anti-nociceptive. As such this data suggests sunobinop has potential utility in treatment of pain associated with IC. Source of Funding: Imbrium Therapeutics L.P. a subsidiary of Purdue Pharmaceuticals L.P. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e152 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Garth Whiteside More articles by this author Stamford More articles by this author CT More articles by this author Celine Auge More articles by this author Philippe Lluel More articles by this author Expand All Advertisement PDF downloadLoading ...