Purinergic P2X7 receptors as therapeutic targets in interstitial cystitis/bladder pain syndrome; key role of ATP signaling in inflammation

Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic lower urinary tract condition. Patients with IC/BPS suffer from debilitating pain and urinary urgency. The underlying etiology of IC/BPS is unknown and as such current treatments are mostly symptomatic with no real cure. Many theories have been proposed to describe the etiology of IC/BPS, but this review focuses on the role of inflammation. In IC/BPS patients, the permeability of the urothelium barrier is compromised and inflammatory cells infiltrate the bladder wall. There are increased levels of many inflammatory mediators in patients with IC/BPS and symptoms such as pain and urgency that have been associated with the degree of inflammation. Recent evidence has highlighted the role of purinergic receptors, specifically the P2X7 receptor, in the process of inflammation. The results from studies in animals including cyclophosphamide-induced hemorrhagic cystitis strongly support the role of P2X7 receptors in inflammation. Furthermore, the deletion of the P2X7 receptor or antagonism of this receptor significantly reduces inflammatory mediator release from the bladder and improves symptoms. Research results from IC/BPS patients and animal models of IC/BPS strongly support the crucial role of inflammation in the pathophysiology of this painful disease. Purinergic signaling and purinergic receptors, especially the P2X7 receptor, play an undisputed role in inflammation. Purinergic receptor antagonists show positive results in treating different symptoms of IC/BPS.

P2X7 Receptor Blockade Protects Against Acrolein-Induced Bladder Damage: A Potential New Therapeutic Approach for the Treatment of Bladder Inflammatory Diseases

“…The P2X7 receptors have recently been hypothesized to be involved in bladder cystitis including IC/BPS (Taidi et al, 2019) due to their important role in inflammation (De Marchi et al, 2016). It is suggested that, under pathophysiological conditions, a higher concentration of extracellular ATP (Sun and Chai, 2006) causes prolonged activation of the P2X7 receptor, resulting in extreme permeability of the cell membrane to ions (Hattori and Gouaux, 2012) and formation of a large membrane pore.…”

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

“…We used the same concentration of LX as that in the mouse model (4.5 mM, 100 μm) [ 4 ], but we increased the volume of LX (4.5 mM, 200 μm) in the current study after considering the bladder volume of rats [ 30 ]. A potential strength of this study is the use of a TLR7-induced Hunner-type IC rat model system compared with other commonly used IC/BPS model systems induced with cyclophosphamide [ 31 , 32 ], lipopolysaccharide [ 33 ], hydrochloric acid (HCl) [ 7 , 13 ], uroplakin [ 14 , 29 ] and ketamine [ 9 ].…”

Urinary Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome and Its Impact on Therapeutic Outcome

“…In cystoscopy, IC/BPS is diagnosed when the bladder has been filled to its maximum capacity (at a pressure of 80–100 cm H 2 O). In IC/BPS patients, mucosal splitting, glomerulations, and Hunner ulcers are frequently observed mucosal damage in IC/BPS [ 101 ]. In order to diagnosis of the HIC/BPS or NHIC/BPS, cystoscopy is recommended to examine the bladder mucosa after bladder filling and determine the presence or absence of Hunner lesions [ 102 , 103 ].…”

“…ATP is released from urothelium in response to bladder stretch and could act on urothelial purinergic receptors. Patients with IC/BPS have increased afferent nerve density and ATP release, which might affect the symptoms of pain, urgency and frequency [ 101 ]. The expression of both P2X and P2Y receptors in nerve fibers and myofibroblasts, located close to urothelium and detrusor muscle, and the sensitivity of these receptors to ATP suggest that ATP release may influence function of myofibroblasts and afferent nerve endings [ 158 ].…”

“…Clinically, inhibition of efferent ATP release treated with BoNT-A could ameliorate acute pain and urgency sensation [ 162 ]. Purinergic receptor antagonists show positive results in the treatment of different symptoms of IC/BPS [ 101 ]. In IC/BPS patients, elevation of urinary ATP level and increase stretch-activated ATP released by bladder urothelium has been reported, suggesting augmented purinergic signaling in IC/BPS bladders [ 163 ].…”