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Nature Reviews. Urology Oct 2014Urinary incontinence adversely affects quality of life and results in an increased financial burden for the elderly. Accumulating evidence suggests a connection between... (Review)
Review
Urinary incontinence adversely affects quality of life and results in an increased financial burden for the elderly. Accumulating evidence suggests a connection between neurotrophins, such as brain-derived neurotrophic factor (BDNF), and lower urinary tract function, particularly with regard to normal physiological function and the pathophysiological mechanisms of stress urinary incontinence (SUI) and bladder pain syndrome/interstitial cystitis (BPS/IC). The interaction between BDNF and glutamate receptors affects both bladder and external urethral sphincter function during micturition. Clinical findings indicate reduced BDNF levels in antepartum and postpartum women, potentially correlating with postpartum SUI. Experiments with animal models demonstrate that BDNF is decreased after simulated childbirth injury, thereby impeding the recovery of injured nerves and the restoration of continence. Treatment with exogenous BDNF facilitates neural recovery and the restoration of continence. Serotonin and noradrenaline reuptake inhibitors, used to treat both depression and SUI, result in enhanced BDNF levels. Understanding the neurophysiological roles of BDNF in maintaining normal urinary function and in the pathogenesis of SUI and BPS/IC could lead to future therapies based on these mechanisms.
Topics: Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Cystitis, Interstitial; Female; Humans; Quality of Life; Receptors, Glutamate; Urethra; Urinary Bladder; Urinary Incontinence; Urinary Incontinence, Stress; Urinary Tract; Urination
PubMed: 25224451
DOI: 10.1038/nrurol.2014.244 -
Biomolecules Feb 2023The unclear etiology and pathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS) are responsible for the lack of effective treatment and the poor patient...
The unclear etiology and pathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS) are responsible for the lack of effective treatment and the poor patient prognosis. Various studies show that chronic inflammation and immune responses are important factors contributing to the pathogenesis of IC/BPS. The process of immunogenic cell death (ICD) involves both the immune response and inflammatory process, and the involvement of ICD in IC/BPS pathogenesis has not been explored. Two IC/BPS transcriptome datasets collected from the Gene Expression Omnibus (GEO) database were used to identify distinct ICD-associated molecular patterns (IAMPs). IAMPs and IC/BPS subtypes were found to be related. The inflammatory immune microenvironments (IIME) in different IAMPs were studied. The potential mechanism by which the interleukin 17 receptor A (IL17RA) influences IC/BPS was examined using in vitro assays. The expression of ICD-related genes (IRGs) was upregulated in IC/BPS bladders, compared with normal bladders. Disease prediction models, based on differentially expressed IRGs, could accurately predict IC/BPS. The IC/BPS patients had two distinct IAMPs, each with its own subtype and clinical features and association with remodeling IIME. IL17RA, a well-established IC/BPS bladder biomarker, mediates both the inflammatory insult and the protective responses. In summary, the current study identified different IAMPs in IC/BPS, which may be involved in the pathogenesis of IC/BPS by remodeling the IIME. The chronic inflammatory process in IC/BPS may be prolonged by IL17RA, which could mediate both pro- and anti-inflammatory responses. The IL17RA-associated pathway may play a significant role in the development of IC/BPS and can be used as a therapeutic target.
Topics: Humans; Cystitis, Interstitial; Receptors, Interleukin-17; Immunogenic Cell Death; Urinary Bladder; Inflammation
PubMed: 36979355
DOI: 10.3390/biom13030421 -
Taiwanese Journal of Obstetrics &... Jun 2018To investigate urinary and psychological symptoms in patients with interstitial cystitis/bladder pain syndrome (IC/BPS) after intravesical hyaluronic acid (HA) treatment.
OBJECTIVE
To investigate urinary and psychological symptoms in patients with interstitial cystitis/bladder pain syndrome (IC/BPS) after intravesical hyaluronic acid (HA) treatment.
MATERIALS AND METHODS
Thirty patients with newly diagnosed with IC/BPS undergoing 4 weekly intravesical HA instillations followed by 5 monthly instillations were recruited. Pre-treatment evaluation included a urinalysis and urinary culture, a 3-day voiding diary, and cystoscopy with hydrodistention of the bladder. Questionnaires containing hospital anxiety and depression scale (HADS), O'Leary-Sant score, Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire (PISQ-12), and a pain visual analog scale were completed before and after treatment. Thirty age-matched, asymptomatic women were recruited as controls for assessing HADS scores, and comparison of urinary and psychological symptoms in patients before and after HA treatment.
RESULTS
The mean age (range 25-71 years old) and symptomatic duration (range 1-11 years) were 47 and 4.5, respectively. When compared with the control group, patients with IC/BPS had a significant increase in HADS depression subscale score and total score. Frequency, nocturia, bladder capacity, IC symptom and problem index scores, and pain score improved after 6 months of intravesical HA treatment. After HA treatment, 73% (n = 22) of patients showed improvement in their urological symptoms, but no significant changes were found in their HADS and PISQ-12 scores.
CONCLUSIONS
Bladder pain and lower urinary tract symptoms in patients with IC/BPS may improve after a 6-month intravesical HA treatment. However, no significant changes in their psychological and sexual functional scores were found.
Topics: Adjuvants, Immunologic; Administration, Intravesical; Adult; Anxiety; Case-Control Studies; Cystitis, Interstitial; Depression; Female; Humans; Hyaluronic Acid; Middle Aged; Nocturia; Pain; Pain Measurement; Prospective Studies; Surveys and Questionnaires; Urinary Bladder
PubMed: 29880165
DOI: 10.1016/j.tjog.2018.04.006 -
Drug Design, Development and Therapy 2021Hyperalgesia and bladder overactivity are two main symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS). Cannabinoid receptors participate in the modulation...
PURPOSE
Hyperalgesia and bladder overactivity are two main symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS). Cannabinoid receptors participate in the modulation of pain and bladder function. GPR18, a member of the cannabinoid receptor family, also participates in the regulation of pain and bladder function, but its underlying mechanisms are unknown. In this work, we sought to study the role of GPR18 in IC/BPS.
METHODS
A rat model of IC/BPS was established with cyclophosphamide (CYP). Paw withdrawal threshold (PWT) measurement and cystometry were used to evaluate pain and bladder function, respectively. RT-PCR, Western blotting and immunofluorescence were used to assess the expression and distribution of GPR18. The role of GPR18 in pain and bladder function was studied by intrathecal injection of resolvin D2 (RvD2, a GPR18 agonist) and O-1918 (a GPR18 antagonist). Calcium imaging was used to study the relationship between GPR18 and TRPV1.
RESULTS
A rat model of IC/BPS, which exhibited a decreased PWT and micturition interval, was successfully established with CYP. The mRNA and protein expression of GPR18 was reduced in the bladder and dorsal root ganglia (DRG) in rats with CYP-induced cystitis. Intrathecal injection of RvD2 increased the PWT and micturition interval. However, O-1918 blocked the therapeutic effect of RvD2. GPR18 was present in bladder afferent nerves and colocalized with TRPV1 in DRG, and RvD2 decreased capsaicin-induced calcium influx in DRG.
CONCLUSION
Activation of GPR18 by RvD2 alleviated hyperalgesia and improved bladder function, possibly by inhibiting TRPV1 in rats with CYP-induced cystitis.
Topics: Animals; Cyclophosphamide; Cystitis; Disease Models, Animal; Docosahexaenoic Acids; Female; Pain; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; TRPV Cation Channels; Urinary Bladder
PubMed: 34815664
DOI: 10.2147/DDDT.S329507 -
Scientific Reports Feb 2019Menstrual pain, also known as dysmenorrhea, is a leading risk factor for bladder pain syndrome (BPS). A better understanding of the mechanisms that predispose...
Menstrual pain, also known as dysmenorrhea, is a leading risk factor for bladder pain syndrome (BPS). A better understanding of the mechanisms that predispose dysmenorrheic women to BPS is needed to develop prophylactic strategies. Abnormal autonomic regulation, a key factor implicated in BPS and chronic pain, has not been adequately characterized in women with dysmenorrhea. Thus, we examined heart rate variability (HRV) in healthy (n = 34), dysmenorrheic (n = 103), and BPS participants (n = 23) in their luteal phase across a bladder-filling task. Both dysmenorrheic and BPS participants reported increased bladder pain sensitivity when compared to controls (p's < 0.001). Similarly, dysmenorrheic and BPS participants had increased heart rate (p's < 0.01), increased diastolic blood pressure (p's < 0.01), and reduced HRV (p's < 0.05) when compared to controls. Dysmenorrheic participants also exhibited little change in heart rate between maximum bladder capacity and after micturition when compared to controls (p = 0.013). Our findings demonstrate menstrual pain's association with abnormal autonomic activity and bladder sensitivity, even two weeks after menses. Our findings of autonomic dysfunction in both early episodic and chronic visceral pain states points to an urgent need to elucidate the development of such imbalance, perhaps beginning in adolescence.
Topics: Adult; Autonomic Nervous System; Blood Pressure; Case-Control Studies; Dysmenorrhea; Female; Heart Rate; Humans; Pain Measurement; Pain Threshold; Urinary Bladder; Urination; Young Adult
PubMed: 30778114
DOI: 10.1038/s41598-019-38545-3 -
PloS One 2018Electron microscopy (EM) characteristics of the urothelium in interstitial cystitis/bladder pain syndrome (IC/BPS) and their association with clinical condition are... (Clinical Trial)
Clinical Trial
BACKGROUND
Electron microscopy (EM) characteristics of the urothelium in interstitial cystitis/bladder pain syndrome (IC/BPS) and their association with clinical condition are unclear.
METHODS
Ten IC/BPS patients who were admitted for hydrodistention and 5 patients with stress urinary incontinence (control patients) were enrolled. All patients provided detailed clinical histories and underwent urodynamic studies. Cystoscopic bladder biopsies were obtained and processed for transmission EM (TEM) and scanning EM (SEM). The severity of the urothelium findings was graded on a 4-point scale (0: none, 1: mild, 2: moderate, and 3: severe). The EM findings between IC/BPS and control patients were compared; the results were analyzed using the chi-square test.
RESULTS
Compared with the urothelium of control patients, the urothelium of IC/BPS patients had more severe defects of the urothelial cell layers and integrity of umbrella cells in TEM (p = 0.045 and 0.01, respectively). In SEM, umbrella cell pleomorphism increased and microplicae of the cell membrane decreased in the IC/BPS group, and both were more severe than in the control group (p = 0.022 and 0.007, respectively). The patients with moderate to severe defects of umbrella cell integrity had more severe bladder pain and smaller maximal bladder capacity (MBC) (both p = 0.010). Patients with moderate to severe defects in microplicae of the cell membrane had smaller cystometric bladder capacity and MBC (p = 0.037 and 0.047, respectively).
CONCLUSIONS
The results revealed significant urothelium defects in IC/BPS, especially in the umbrella cells. Defects of umbrella cells may play an important role in the pathogenesis of IC/BPS.
Topics: Adult; Aged; Cystitis, Interstitial; Female; Humans; Male; Microscopy, Electron; Middle Aged; Pain; Urinary Bladder; Urinary Incontinence, Stress; Urothelium
PubMed: 29879217
DOI: 10.1371/journal.pone.0198816 -
Toxins Mar 2020Bladder oversensitivity arises from several different conditions involving the bladder, bladder outlet, systemic or central nervous system diseases. Increase of the... (Review)
Review
Bladder oversensitivity arises from several different conditions involving the bladder, bladder outlet, systemic or central nervous system diseases. Increase of the bladder sensation results from activation of the sensory receptors in the urothelial cells or suburothelial tissues. Medical treatment targeting the overactive bladder (OAB) or interstitial cystitis (IC) might relieve oversensitive bladder symptoms (frequency, urgency and pain) in a portion of patients, but a certain percentage of patients still need active management. Botulinum toxin A (BoNT-A) has been demonstrated to have anti-inflammatory and antinociceptive effects in bladder sensory disorders and has been shown effective in the reduction of bladder oversensitivity and the increase of functional bladder capacity. For patients with OAB, urgency and urinary incontinence improved, while in patients with IC, bladder pain could be relieved in association with reduction of bladder oversensitivity after BoNT-A intravesical injection. Histological evidence has confirmed the therapeutic mechanism and clinical efficacy of intravesical BoNT-A injection on patients with OAB or IC. Bladder oversensitivity can also be relieved with the instillation of liposome encapsulated BoNT-A or low energy show waves (LESWs), which enable the BoNT-A molecule to penetrate into the urothelium and suburothelial space without affecting the detrusor contractility. Liposome encapsulated BoNT-A or combined LESWs and BoNT-A instillation might be future treatment alternatives for bladder oversensitivity in sensory bladder disorders.
Topics: Animals; Botulinum Toxins, Type A; Humans; Injections; Urinary Bladder; Urinary Bladder Diseases
PubMed: 32182780
DOI: 10.3390/toxins12030166 -
Cellular Physiology and Biochemistry :... 2016To assess the efficacy of intravesical hyaluronic acid (HA) and HA/chondroitin sulfate (CS) instillation in patients with interstitial cystitis/painful bladder syndrome... (Meta-Analysis)
Meta-Analysis Review
Systematic Review and Meta-Analysis of Intravesical Hyaluronic Acid and Hyaluronic Acid/Chondroitin Sulfate Instillation for Interstitial Cystitis/Painful Bladder Syndrome.
BACKGROUND/AIMS
To assess the efficacy of intravesical hyaluronic acid (HA) and HA/chondroitin sulfate (CS) instillation in patients with interstitial cystitis/painful bladder syndrome by systematic review and meta-analysis.
METHODS
A systematic literature search was performed using the keywords: 'interstitial cystitis' or 'painful bladder syndrome' or 'bladder pain syndrome' and 'hyaluronic acid', up to March 31, 2016. The primary outcome was visual analogue scale related pain symptom (VAS). Secondary outcomes were the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI) and Problem Index (ICPI), frequency, nocturia, bladder volume, and voided urine volume.
RESULTS
Ten articles involving 390 patients were retrieved and assessed in analysis. A significant improvement in mean VAS on fixed-effect and random-effect models (mean difference [MD] -3.654, 95% confidence interval [CI] -3.814 to -3.495, and MD -3.206, 95% CI -4.156 to -2.257, respectively) was found. Significant improvements were found in the ICSI (MD -3.223, 95% CI -4.132 to -2.315) and ICPI (MD -2.941, 95% CI -3.767 to -2.116). Similarly, the other outcomes were significantly improved.
CONCLUSION
Intravesical HA and HA/CS instillation improved pain symptom, quality of life, and other outcomes and could be included as therapeutic modality of interstitial cystitis/painful bladder syndrome.
Topics: Administration, Intravesical; Chondroitin Sulfates; Cystitis, Interstitial; Female; Humans; Hyaluronic Acid; Nocturia; Organ Size; Pain Management; Pain Measurement; Quality of Life; Treatment Outcome; Urinary Bladder
PubMed: 27627755
DOI: 10.1159/000447863 -
Neuroscience Mar 2017Painful events early in life have been shown to increase the incidence of interstitial cystitis/painful bladder syndrome in adulthood. However, the intrinsic mechanism...
Painful events early in life have been shown to increase the incidence of interstitial cystitis/painful bladder syndrome in adulthood. However, the intrinsic mechanism is not well studied. We previously reported that neonatal bladder inflammation causes chronic visceral hypersensitivity along with molecular disruption of spinal GABAergic system in rats. The present study investigates whether these molecular changes affect the integrative function and responses of bladder-sensitive primary afferent and spinal neurons. Neonatal bladder inflammation was induced by intravesicular injection of zymosan during postnatal (P) days 14-16. In adulthood (P60), the viscero-motor response (VMR) to visceral stimuli was significantly inhibited by intrathecal (i.t) HZ166 (GABA agonist) only in neonatally saline-treated, but not in neonatally zymosan-treated rats. HZ166 significantly inhibited the responses of bladder-responsive lumbosacral (LS) spinal neurons to urinary bladder distension (UBD) and slow infusion (SI) in neonatally saline-treated rats. Similar results were also observed in naïve adult rats where HZ166 produced significant inhibition of bladder-responsive spinal neurons. However, HZ166 did not inhibit responses of UBD-responsive spinal neurons from neonatally zymosan-treated rats. The drug did not attenuate the responses of UBD-sensitive pelvic nerve afferent (PNA) fibers to UBD and SI in either group of rats tested. Immunohistochemical studies showed a significantly lower level of GABA receptor expression in the LS spinal cord of neonatally zymosan-treated rats compared to saline-treated rats. These findings indicate that neonatal bladder inflammation leads to functional and molecular alteration of spinal GABA receptor subtypes, which may result in chronic visceral hyperalgesia in adulthood.
Topics: Animals; Animals, Newborn; Benzodiazepines; Colon; Cystitis, Interstitial; Female; GABA-A Receptor Agonists; Imidazoles; Lumbosacral Region; Neurons; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Spinal Cord; Urinary Bladder; Visceral Pain; Zymosan
PubMed: 28126369
DOI: 10.1016/j.neuroscience.2017.01.021 -
Physiological Reviews Jan 2014The tachykinins, exemplified by substance P, are one of the most intensively studied neuropeptide families. They comprise a series of structurally related peptides that... (Review)
Review
The tachykinins, exemplified by substance P, are one of the most intensively studied neuropeptide families. They comprise a series of structurally related peptides that derive from alternate processing of three Tac genes and are expressed throughout the nervous and immune systems. Tachykinins interact with three neurokinin G protein-coupled receptors. The signaling, trafficking, and regulation of neurokinin receptors have also been topics of intense study. Tachykinins participate in important physiological processes in the nervous, immune, gastrointestinal, respiratory, urogenital, and dermal systems, including inflammation, nociception, smooth muscle contractility, epithelial secretion, and proliferation. They contribute to multiple diseases processes, including acute and chronic inflammation and pain, fibrosis, affective and addictive disorders, functional disorders of the intestine and urinary bladder, infection, and cancer. Neurokinin receptor antagonists are selective, potent, and show efficacy in models of disease. In clinical trials there is a singular success: neurokinin 1 receptor antagonists to treat nausea and vomiting. New information about the involvement of tachykinins in infection, fibrosis, and pruritus justifies further trials. A deeper understanding of disease mechanisms is required for the development of more predictive experimental models, and for the design and interpretation of clinical trials. Knowledge of neurokinin receptor structure, and the development of targeting strategies to disrupt disease-relevant subcellular signaling of neurokinin receptors, may refine the next generation of neurokinin receptor antagonists.
Topics: Animals; Humans; Intestinal Mucosa; Muscle Contraction; Muscle, Smooth; Receptors, Tachykinin; Tachykinins; Urinary Bladder
PubMed: 24382888
DOI: 10.1152/physrev.00031.2013