Rationale for the Use of 8‐Aminoguanine for the Management of Cystitis

Bladder pain and associated lower urinary tract symptoms (LUTSs) are hallmark features of interstitial cystitis/bladder pain syndrome (IC/BPS) and hemorrhagic cystitis (HC). IC/BPS is characterized by bladder‐based pain and irritative bladder symptoms, with or without gross inflammatory changes (Hunner lesions) in the bladder wall, and the absence of well‐described causes such as infection or neoplastic disease. The clinical features of HC are similar to IC/BPS, but in this instance, they are always associated with visible inflammatory disease with known etiologies such as infection or a complication of radiation and/or chemotherapy. While progress has been made in defining the spinal circuits that gate pain signals emanating from the pelvic viscera, lack of a clear understanding of the mechanisms leading to cystitis‐induced visceral pain and lack of validated therapeutic targets for cystitis are a source of frustration for clinicians treating conditions such as IC/BPS and HC and their patients. This review will focus on an emerging therapy for cystitis, namely 8‐aminoguanine (8‐AG), which inhibits the enzyme purine nucleoside phosphorylase (PNPase). PNPase is important for metabolism of “tissue‐protective” purine metabolites into “tissue‐damaging” purines that generate free radicals. IC/BPS patients without and with Hunner lesions exhibit a dysregulation of purine metabolism, with elevated levels of urotoxic purine metabolites compared to healthy controls. Rodents treated with cyclophosphamide are a standard animal model for cystitis and exhibit multiple abnormalities, including increased urinary frequency, neural mechanosensitivity, suppression of pain‐reducing purines, and increased urothelial inflammation/damage. Orally administered 8‐AG prevents all observed histological, structural, biochemical, and physiological abnormalities in cyclophosphamide‐induced cystitis. These findings demonstrate that 8‐AG holds promise for reducing pain and preventing bladder damage for patients with cystitis‐associated pain and LUTS.