Article

Interstitial cystitis: Bladder pain and beyond

Tufts University School of Medicine, Department of Pharmacology and Experimental Therapeutics, Experimental Therapeutics 136 Harrison Avenue, Boston, MA 02111, USA.
Expert Opinion on Pharmacotherapy (Impact Factor: 3.09). 01/2009; 9(17):2979-94. DOI: 10.1517/14656560802519845
Source: PubMed

ABSTRACT Interstitial cystitis is characterized by over 6 months of chronic pain, pressure and discomfort felt in the lower pelvis or bladder. It is often relieved with voiding, along with daytime frequency and nocturia in the absence of a urinary tract infection. Interstitial cystitis occurs primarily in females including adolescents and its diagnosis is still one of exclusion. It is now recognized as a serious medical condition associated with significant disability.
The aim of this paper was to review the pathogenesis and treatment of interstitial cystitis with emphasis on new pathogenetic trends and therapeutic modalities.
About 713 mostly original papers were reviewed in Medline from 1990 to August. 2008. All authors independently reviewed the literature. Large, double-blind, placebo-controlled, clinical trials were few and the medical histories of the patients used varied considerably making conclusions difficult. Promising pilot trials turned out mostly negative on follow-up.
Increasing evidence of co-morbid diseases, neurogenic inflammation and the effect of stress are promising as new targets for pathophysiology. No new effective treatments have emerged. Oral pentosanpolysulfate, amitriptyline, hydroxyzine and quercetin, as well as intravesical heparin/bicarbonate/lidocaine solutions, are still used with variable success. Some pilot open-label trials presented encouraging findings.
Interstitial cystitis contributes substantially to chronic pelvic pain and to poor quality of life. Oral or intravesical administration of solutions containing sodium hyaluronate, chondroitin sulfate and quercetin to both reduce bladder inflammation and 'replenish' the glycosaminoglycan layer should be tried. There is a clear need for therapeutic modalities. New potential translational research areas are suggested.

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    • "Interstitial cystitis (IC) is a chronic disease caused by inflammation of the bladder wall (Theoharides et al., 2008). The clinical features of interstitial cystitis are often associated with a constant condition of pelvic pain, recurrent urinary frequency and nocturia (Hanno, 2002; Hanno et al., 2009). "
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    ABSTRACT: Interstitial cystitis is a debilitating bladder inflammation disorder. To date, the understanding of the causes of interstitial cystitis remains largely fragmentary and there is no effective treatment available. Recent experimental results have shown a functional role of the endocannabinoid system in urinary bladder. In this study, we evaluated the anti-inflammatory effect of selective cannabinoid CB1 and CB2 receptor agonists in a mouse model of interstitial cystitis. Bladder inflammation was induced in mice by lipopolysaccharide (LPS) and whole bladders were removed 24h later. LPS induced a significant increase of the contractile amplitude in spontaneous activity and a hypersensitivity to exogenous acetylcholine-induced contraction of whole-isolated bladder. Next, we evaluated the anti-inflammatory activity of cannabinoidergic compounds by pretreating mice with CB1 or CB2 selective agonist compounds, respectively ACEA and JWH015. Interestingly, JWH015, but not ACEA, antagonized LPS-induced bladder inflammation. Additionally, anti-inflammatory activity was studied by evaluation, leukocytes mucosa infiltration, myeloperoxidase activity, and mRNA expression of pro-inflammatory interleukin (IL-1α and IL-1β), tumor necrosis factor-alpha (TNF-α) and cannabinoid CB1 and CB2 receptors. JWH015 significantly decreased leukocytes infiltration in both submucosa and mucosa, as well as the myeloperoxydase activity, in LPS treated mice. JWH015 reduced mRNA expression of IL-1α, IL-1β, and TNF-α. LPS treatment increased expression of bladder CB2 but not CB1 mRNA. Taken together, these findings strongly suggest that modulation of the cannabinoid CB2 receptors might be a promising therapeutic strategy for the treatment of bladder diseases and conditions characterized by inflammation, such as interstitial cystitis.
    European journal of pharmacology 02/2014; 729(1). DOI:10.1016/j.ejphar.2014.02.013 · 2.68 Impact Factor
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    • "Interstitial cystitis or painful bladder syndrome is an idiopathic disease, presenting with bladder pain and urinary frequency or urgency (Kelada and Jones, 2007). The bladder pain accompanying interstitial cystitis is regional, chronic and spread over the lower pelvic and suprapubic area and mimics neuropathic pain (Theoharides et al., 2008). Interestingly, there is evidence that NaHS administered intravesically produces changes in urodynamic parameters after chemical disruption of the urothelial barrier in rats, although the mechanisms underlying the effect of NaHS in vivo have yet to be analysed (Streng et al., 2008). "
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    ABSTRACT: BACKGROUND AND PURPOSE Hydrogen sulfide (H(2) S), generated by enzymes such as cystathionine-γ-lyase (CSE) from L-cysteine, facilitates pain signals by activating the Ca(v) 3.2 T-type Ca(2+) channels. Here, we assessed the involvement of the CSE/H(2) S/Ca(v) 3.2 pathway in cystitis-related bladder pain. EXPERIMENTAL APPROACH Cystitis was induced by i.p. administration of cyclophosphamide in mice. Bladder pain-like nociceptive behaviour was observed and referred hyperalgesia was evaluated using von Frey filaments. Phosphorylation of ERK in the spinal dorsal horn was determined immunohistochemically following intravesical administration of NaHS, an H(2) S donor. KEY RESULTS Cyclophosphamide caused cystitis-related symptoms including increased bladder weight, accompanied by nociceptive changes (bladder pain-like nociceptive behaviour and referred hyperalgesia). Pretreatment with DL-propargylglycine, an inhibitor of CSE, abolished the nociceptive changes and partly prevented the increased bladder weight. CSE protein in the bladder was markedly up-regulated during development of cystitis. Mibefradil or NNC 55-0396, blockers of T-type Ca(2+) channels, administered after the symptoms of cystitis appeared, reversed the nociceptive changes. Further, silencing of Ca(v) 3.2 protein by repeated intrathecal administration of mouse Ca(v) 3.2-targeting antisense oligodeoxynucleotides also significantly attenuated the nociceptive changes, but not the increased bladder weight. Finally, the number of cells staining positive for phospho-ERK was increased in the superficial layer of the L6 spinal cord after intravesical administration of NaHS, an effect inhibited by NNC 55-0396. CONCLUSION AND IMPLICATIONS Endogenous H(2) S, generated by up-regulated CSE, caused bladder pain and referred hyperalgesia through the activation of Ca(v) 3.2 channels, one of the T-type Ca(2+) channels, in mice with cyclophosphamide-induced cystitis.
    British Journal of Pharmacology 05/2012; 167(4):917-28. DOI:10.1111/j.1476-5381.2012.02060.x · 4.99 Impact Factor
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    • "Further application of chondroitin sulphate in humans refers to eye surgery, where chondroitin sulphate is topically applied for phacoemulsification postoperatively (Praveen et al., 2008). In humans, it has also been reported that instillation of chondroitin sulphate effectively reduced all symptoms in patients with chronic forms of cystitis (Nordling and van Ophoven, 2008), that oral or intravesical administration of chondroitin sulphate reduced bladder inflammation and 'replenished' the GAG layer (Theoharides et al., 2008) and that intravesical administration of chondroitin sulphate is regarded as a safe and efficacious method of treatment of patients with interstitial cystitis/painful bladder syndrome (Porru et al., 2008). Further effects of chondroitin sulphate are associated in humans with coagulation. "
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    ABSTRACT: The extracellular matrix (ECM) plays a significant role in the structure and function of the lung. The ECM is a three-dimensional fibre mesh, comprised of various interconnected and intercalated macromolecules, among which are the glycosaminoglycans (GAG). GAG are long, linear and highly charged, heterogeneous polysaccharides that are composed of a variable number of repeating disaccharide units (macromolecular sugars) and most of them, as their name implies, have a sweet taste. In the lung, GAG support the structure of the interstitium, the subepithelial tissue and the bronchial walls, and are secreted in the airway secretions. Besides maintaining lung tissue structure, GAG also play an important role in lung function as they regulate hydration and water homeostasis, modulate the inflammatory response and influence lung tissue repair and remodelling. However, depending on their size and/or degree of sulphation, and their immobilization or solubilization in the ECM, specific GAG in the lung either live up to their sweet taste/name, supporting normal lung physiology, or they are associated to 'bitter' effects, related to lung pathology. The present review discusses the biological role of GAG in the lung as well as the involvement of these molecules in various respiratory diseases. Given the great structural diversity of GAG, understanding the changes in GAG expression that occur in lung diseases may lead to novel targets for pharmacological intervention in order to prevent and/or to treat a range of lung diseases.
    British Journal of Pharmacology 07/2009; 157(7):1111-27. DOI:10.1111/j.1476-5381.2009.00279.x · 4.99 Impact Factor
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