Chronic visceral pain disorders, such as interstitial cystitis/bladder pain syndrome (IC/BPS), are difficult to treat, and response to treatment is disappointing.  The cause of IC/BPS is unknown, and IC/BPS is difficult to diagnose and has no compelling therapeutic targets.  Nonetheless, patients with IC/BPS express biomarkers linked to increased oxidative stress, and oxidative stress is known to trigger responses that can exacerbate generalized pain syndromes by enhancing nociceptive signaling and promoting oxidative damage. Despite an underlying role for mitochondrial dysregulation and increased reactive oxygen species (ROS) in the pathophysiology of functional pain disorders such as IC/BPS, antioxidants are not able to reverse established oxidative damage. However, emerging evidence suggests that alterations in the enzyme purine nucleoside phosphorylase (PNPase) may participate in oxidative injury and cellular damage. In this regard, PNPase transforms inosine to hypoxanthine and guanosine to guanine. Hypoxanthine and guanine are subsequently converted to xanthine via xanthine oxidase and guanine deaminase, respectively. Inosine and guanosine are ‘uroprotective’ purines and both hypoxanthine and xanthine are urotoxic purines and sources of ROS. This suggests that PNPase may be a target for treatment of IC/BPS using a non-opioid based PNPase inhibitor. Because there are no satisfactory treatments for IC/BPS, our research program is dedicated to validating PNPase as a target for treatment of IC/BPS.

We tested 2 hypotheses: (H1) IC/BPS as well as Hunner’s patients exhibit purine dysregulation, with higher levels of tissue-damaging purine metabolites hypoxanthine and xanthine; and (H2) the degree of purine dysregulation correlates with pain scores (using the pelvic pain and urgency/frequency patient symptom scale (BPIC-SS). De-identified human urine samples were obtained (with IRB approval and informed consent) from control subjects and patients diagnosed with IC/BPS or Hunner’s lesions.  We measured the urinary purine metabolome by high-performance liquid chromatography-tandem mass spectrometry.

In both IC/BPS and Hunner’s lesion patients we observed significantly elevated levels of inosine and guanosine and their urotoxic downstream metabolites, hypoxanthine and xanthine. Moreover, these changes were highly correlated with elevated pain scores in patients diagnosed with IC/BPS, but not Hunner’s lesion patients.

Our results demonstrate that levels of urotoxic purine metabolites are increased in urine of IC/BPS and Hunner’s lesion patients.  Since inosine and guanosine levels are also increased, our findings suggest that the higher levels of hypoxanthine and xanthine are driven by increased availability of upstream substrates. This implies that inhibition of PNPase in such patients may be beneficial because inhibition of PNPase in the setting of increased flux of purines through the inosinehypoxanthinexanthine and guanosinexanthine pathways would cause the accumulation of uroprotective inosine and guanosine, while simultaneously reducing levels of urotoxic hypoxanthine and xanthine. This could lead to a reduction in pain symptoms in IC/BPS patients.  While there was a lack of correlation between elevated urotoxic metabolites and pain scores in patients with Hunner’s lesion, this may reflect a difference in pain characteristics in Hunner’s patients.

Here we report for the first time that IC/BPS patients (with and without Hunner lesions) exhibit a dysfunctional purine metabolome with increased indicators of oxidative stress.  Our data suggest that treating such patients with an inhibitor of PNPase could be beneficial by reducing free radical formation and oxidative stress, thereby minimizing painful bladder symptoms.