Effective treatment of interstitial cystitis/bladder pain syndrome (IC/BPS) has been elusive due to the multifactorial nature of the condition and lack of clarity on the pathological origins of the condition. There is evidence that potentiation of the nitric oxide-soluble guanylate cyclase (sGC) signaling pathway can ameliorate symptoms of bladder inflammation [1] and modulate sensory activity [2].  Accordingly, we examined the potential sites and mechanisms of action in a mouse model of chronic bladder inflammation and the efficacy of treatment with the small molecule sGC activator, cinaciguat.

Adult (2-4 months) C57Bl/6 female mice (Jackson Laboratories) were anesthetized and intravesically instilled with acrolein solution (1 mM) or vehicle (sterile saline) for 15 minutes, once a week for three consecutive weeks. Mice were evaluated for pelvic (tactile and thermal) sensitivity, voiding patterns by urine spot tests before subcutaneous osmotic pumps (ALZET) were implanted to deliver 10 mg/kg/day cinaciguat or vehicle (PEG-400/DMSO) over a two-week period. At the end of treatment, mice were again evaluated for pelvic sensitivity and voiding behavior in metabolic cages before euthanasia and tissue collection. Bladders, urines and blood serum were collected for histological, immunoblot and oxidative stress marker analyses.

Acrolein treated mice given cinaciguat showed a significant decrease in pelvic sensitivity to both tactile and heat sensitivity (figure 1A and 1B) that correlated with decreased bladder wall fibrosis (figure 1C-1E, Masson trichrome stain; pink - cell cytosol, blue - collagen). Urination frequency was increased with acrolein instillation and moderately reduced with cinaciguat treatment (figure 2A) as were the levels of 8-hydroxydeoxyguanine (8-OHdG, oxidative stress marker) in blood serum (figure 2B), but there was no change in the urine 8-OHdG levels (figure 2C).

Increasing sGC activity using cinaciguat ameliorated pelvic sensitivity in acrolein-induced cystitis through direct and/or indirect effects on inflammation, nerve sensitivity and oxidative stress.

There are limited numbers of treatment options for IC/BPS with potentially serious side effects (e.g. pentosan polysulfate) or risk of abuse (e.g. opioids). Targeting the sGC pathway could represent a novel and non-addictive mechanism to ameliorate IC/BPS symptoms.

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Li et al., Neural Regeneration Research, 18(5):996–1003, 2022.