Purine nucleoside phosphorylase inhibition ameliorates age-associated lower urinary tract dysfunctions

Abstract

In the aging population, lower urinary tract (LUT) dysfunction is common and often leads to storage and voiding difficulties classified into overlapping symptom syndromes. Despite prevalence and consequences of these syndromes, LUT disorders continue to be undertreated simply because there are few therapeutic options. LUT function and structure were assessed in aged (>25 months) male and female Fischer 344 rats randomized to oral treatment with a purine nucleoside phosphorylase (PNPase inhibitor) 8-aminoguanine (8-AG) or vehicle for 6 weeks. The bladders of aged rats exhibited multiple abnormalities: tactile insensitivity, vascular remodeling, reduced collagen-fiber tortuosity, increased bladder stiffness, abnormal smooth muscle morphology, swelling of mitochondria, and increases in urodamaging purine metabolites. Treatment of aged rats with 8-AG restored all evaluated histological, ultrastructural, and physiological abnormalities toward that of a younger state. 8-AG is an effective treatment that ameliorates key age-related structural and physiologic bladder abnormalities. Because PNPase inhibition blocks metabolism of inosine to hypoxanthine and guanosine to guanine, likely uroprotective effects of 8-AG are mediated by increased bladder levels of uroprotective inosine and guanosine and reductions in urodamaging hypoxanthine and xanthine. These findings demonstrate that 8-AG has translational potential for treating age-associated LUT dysfunctions and resultant syndromes in humans.

Unfolding New Roles for Guanine-Based Purines and Their Metabolizing Enzymes in Cancer and Aging Disorders

“…In addition, 8-AG decreased urinary levels of hypoxanthine but did not modify those of GUO. The protective effect of 8-AG in the urinary tract has been detected also in age-related urinary incontinence in female rats (Birder et al, 2020a). In this study, the PNP inhibitor reverted mitochondrial injury in urethra smooth and striated muscle and normalized oxidative and nitrosative markers.…”

“…Furthermore, in a murine model of lower urinary tract dysfunction (LUTD), 6 weeks-treatment with a PNP-inhibitor, 8-aminoguanine (8-AG), ameliorated LUTD symptoms (bladder structure and functions alterations and insensitivity) and reversed the age-associated up-regulation of several pro-apoptotic factors such as cleaved caspase-3, p16 and cleaved Poly (ADP-ribose) polymerase (PARP), a downstream effector of oxidative damage (Birder et al, 2020a). In addition, 8-AG decreased urinary levels of hypoxanthine but did not modify those of GUO.…”

Dysregulated Purine Metabolism Contributes to Age-Associated Lower Urinary Tract Dysfunctions

“…In this regard, and as mentioned above, hypoxanthine gives rise to ROS via its downstream metabolism by xanthine oxidase. There is emerging evidence that changes in the activity of PNPase may lead to an abnormal urinary bladder purine metabolome, which in turn causes bladder and urethral inflammation, oxidative injury, and cellular damage [ 7 , 8 ]. Therefore, inhibition of PNPase could be used to manipulate the urinary bladder purine metabolome- by simultaneously increasing uro-protective and decreasing uro-damaging purine metabolites.…”

“…Because PNPase inhibition blocks the metabolism of inosine to hypoxanthine and guanosine to guanine, and because guanine is metabolized to xanthine by guanase, likely the uro-protective effects of PNPase inhibitors in general, and 8-aminoguanine in particular, are mediated by increases in bladder levels of inosine and guanosine (uro-protective purines) and reductions in bladder levels of hypoxanthine and xanthine (uro-damaging purines). Unlike other treatments such as allopurinol (which only targets hypoxanthine metabolism), blocking PNPase increases “uro-protective” precursors (inosine and guanosine) while simultaneously decreasing levels of “uro-toxic” metabolites (hypoxanthine and xanthine) [ 7 ].…”

“…For example, patients with geriatric voiding dysfunction (e.g., impaired contractility) have been shown to exhibit distinctive changes in smooth muscle including cellular atrophy and degeneration [ 26 ]. The aged rat detrusor SM exhibits similar structural alterations as reported in older adults, including SM degeneration, swelling and disruption of the mitochondria and abnormalities in proteins associated with mitochondrial health [ 7 ]. Because mitochondria are considered the powerhouse of organelles, generating 95% of all cellular energy, these pathological changes in mitochondrial structure and function clearly participate in age-related LUTDs.…”