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) for 6 weeks or vehicle. 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 uro-damaging 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 uro-protective effects of 8-AG are mediated by increased bladder levels of uro-protective inosine and guanosine and reductions in uro-damaging hypoxanthine and xanthine. These findings demonstrate 8-AG has translational potential for treating age-associated LUT dysfunctions and resultant syndromes in humans.
Lori A. Birder, Amanda Wolf-Johnston, Alan J. Wein, Fangzhou Cheng, Mara Grove-Sullivan, Anthony J. Kanai, Alan M. Watson, Donna Stolz, Simon C. Watkins, Anne M. Robertson, Diane Newman, Roger R. Dmochowski, Edwin K. Jackson