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.