The lower urinary tract (LUT), including the bladder, urethra and external striated muscle, becomes dysfunctional with age; consequently, many older individuals suffer from lower urinary tract disorders (LUTDs). By compromising urine storage and voiding, LUTDs degrade quality of life for millions of individuals worldwide. Treatments for LUTDs have been disappointing, frustrating both patients and their physicians; however, emerging evidence suggests that partial inhibition of the enzyme purine nucleoside phosphorylase (PNPase) with 8-aminoguanine (an endogenous PNPase inhibitor that moderately reduces PNPase activity) reverses age-associated defects in the LUT and restores the LUT to that of a younger state. Thus, 8-aminoguanine improves LUT biochemistry, structure and function by rebalancing the LUT purine metabolome, making 8-aminoguanine a novel potential treatment for LUTDs.
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Gibson, W. & Wagg, A. Incontinence in the elderly, ‘normal’ ageing, or unaddressed pathology? Nat. Rev. Urol. 14, 440–447 (2017).
Pfisterer, M. H., Griffiths, D. J., Schaefer, W. & Resnick, N. M. The effect of age on lower urinary tract function: a study in women. J. Am. Geriatr. Soc. 54, 405–412 (2006).
Dubeau, C. E. The aging lower urinary tract. J. Urol. 175, S11–S15 (2006).
Chapple, C. R. et al. Lower urinary tract symptoms revisited: a broader clinical perspective. Eur. Urol. 54, 563–569 (2008).
McDonough, R. C. & Ryan, S. T. Diagnosis and management of lower urinary tract dysfunction. Surg. Clin. North Am. 96, 441–452 (2016).
Yoshimura, N. & Chancellor, M. B. Neurophysiology of lower urinary tract function and dysfunction. Rev. Urol. 5, S3–S10 (2003).
Jacobsen, S. J., Girman, C. J. & Lieber, M. M. Natural history of benign prostatic hyperplasia. Urology 58, 5–16 (2001).
Hansen, B. L. Lower urinary tract symptoms (LUTS) and sexual function in both sexes. Eur. Urol. 46, 229–334 (2004).
Azadzoi, K. M. & Siroky, M. B. Mechanisms of lower urinary tract symptoms in pelvic ischemia. J. Biochem. Pharmacol. Res. 1, 64–74 (2013).
Speich, J. E. et al. Are oxidative stress and ischemia significant causes of bladder damage leading to lower urinary tract dysfunction? Neurourol. Urodyn. 39, S16–S22 (2020).
Munro, D. & Treberg, J. R. A radical shift in perspective: mitochondria as regulators of reactive oxygen species. J. Exp. Biol. 220, 1170–1180 (2017).
Duchen, M. R. Mitochondria and calcium: from cell signaling to cell death. J. Physiol. 529, 57–68 (2000).
Bayir, H. & Kagan, V. E. Bench to bedside: mitochondrial injury, oxidative stress and apoptosis. Crit. Care 12, 206 (2008).
Cadenas, E. & Davies, K. J. Mitochondrial free radical generation, oxidative stress and aging. Free Rad. Biol. Med. 29, 222–230 (2000).
Effendi, W. I., Nagano, T., Kobayashi, K. & Nishimura, Y. Focusing on adenosine receptors as a potential targeted therapy in human diseases. Cells 9, 24 (2020).
Jackson, E. K., Gillespie, D. G. & Mi, Z. 8-Aminoguanosine and 8-aminoguanine exert diuretic, natriuretic, glucosuric, and antihypertensive activity. J. Pharmacol. Exp. Ther. 359, 420–435 (2016).
Jackson, E. K. & Tofovic, S. P. Methods for treatment using small molecule potassium-sparing diuretics and natriuretics. US Patent No. 10,729,711 (2020).
Osborne, W. R. & Barton, R. W. A rat model of purine nucleoside phosphorylase deficiency. Immunology 59, 63–67 (1986).
Jackson, E. K. & Mi, Z. 8-Aminoguanosine exerts diuretic, natriuretic, and glucosuric activity via conversion to 8-aminoguanine, yet has direct antikaliuretic effects. J. Pharmacol. Exp. Ther. 363, 358–366 (2017).
Chern, J. W. et al. Nucleosides. 5. Synthesis of guanine and formycin B derivatives as potential inhibitors of purine nucleoside phosphorylase. J. Med. Chem. 36, 1024–1031 (1993).
Jackson, E. K., Mi, Z., Kleyman, T. R. & Cheng, D. 8-Aminoguanine induces diuresis, natriuresis, and glucosuria by inhibiting purine nucleoside phosphorylase and reduces potassium excretion by inhibiting Rac1. J. Am. Heart Assoc. 7, e010085 (2018).
Shibata, S. et al. Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat. Med. 14, 1370–1376 (2008).
Shibata, S. et al. Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway. J. Clin. Invest. 121, 3233–3243 (2011).
Bzowska, A., Kulikowska, E. & Shugar, D. Purine nucleoside phosphorylases: properties, functions, and clinical aspects. Pharmacol. Ther. 88, 349–425 (2000).
Roberts, E. L., Newton, R. P. & Axford, A. T. Plasma purine nucleoside phosphorylase in cancer patients. Clin. Chim. Acta 344, 109–114 (2004).
Silva, R. G. et al. Purine nucleoside phosphorylase activity in rat cerebrospinal fluid. Neurochem. Res. 29, 1831–1835 (2004).
Bortolotti, M., Polito, L., Battelli, M. G. & Bolognesi, A. Xanthine oxidoreductase: one enzyme for multiple physiological tasks. Redox Biol. 41, 101882 (2021).
Snyder, F. F., Yuan, R. G., Bin, J. C., Carter, K. L. & McKay, D. J. Human guanine deaminase: cloning, expression and characterisation. Adv. Exp. Med. Biol. 486, 111–114 (2000).
Birder, L. A. et al. Purine nucleoside phosphorylase inhibition ameliorates age-associated lower urinary tract dysfunctions. JCI Insight 5, 15 (2020).
Haskó, G., Sitkovsky, M. V. & Szabó, C. Immunomodulatory and neuroprotective effects of inosine. Trends Pharmacol. Sci. 25, 152–157 (2004).
Bhattacharyya, S. et al. Oral inosine persistently elevates plasma antioxidant capacity in Parkinson’s disease. Mov. Disord. 31, 417–421 (2016).
Cipriani, S., Bakshi, R. & Schwarzschild, M. A. Protection by inosine in a cellular model of Parkinson’s disease. Neuroscience 274, 242–249 (2014).
Gelain, D. P. et al. Extracellular inosine is modulated by H2O2 and protects Sertoli cells against lipoperoxidation and cellular injury. Free Radic. Res. 38, 37–47 (2004).
Gudkov, S. V., Shtarkman, I. N., Smirnova, V. S., Chernikov, A. V. & Bruskov, V. I. Guanosine and inosine display antioxidant activity, protect DNA in vitro from oxidative damage induced by reactive oxygen species, and serve as radioprotectors in mice. Radiat. Res. 165, 538–545 (2006).
Ruhal, P. & Dhingra, D. Inosine improves cognitive function and decreases aging-induced oxidative stress and neuroinflammation in aged female rats. Inflammopharmacology 26, 1317–1329 (2018).
Teixeira, F. C. et al. Inosine protects against impairment of memory induced by experimental model of Alzheimer disease: a nucleoside with multitarget brain actions. Psychopharmacology 237, 811–823 (2020).
Bellaver, B. et al. Guanosine inhibits LPS-induced pro-inflammatory response and oxidative stress in hippocampal astrocytes through the heme oxygenase-1 pathway. Purinergic Signal. 11, 571–580 (2015).
Gerbatin, R. D. R. et al. Guanosine protects against traumatic brain injury-induced functional impairments and neuronal loss by modulating excitotoxicity, mitochondrial dysfunction, and inflammation. Mol. Neurobiol. 54, 7585–7596 (2017).
Hansel, G. et al. Guanosine protects against cortical focal ischemia. involvement of inflammatory response. Mol. Neurobiol. 52, 1791–1803 (2015).
Luo, Y. et al. Guanosine and uridine alleviate airway inflammation via inhibition of the MAPK and NF-kappaB signals in OVA-induced asthmatic mice. Pulm. Pharmacol. Ther. 69, 102049 (2021).
Zizzo, M. G. et al. Preventive effects of guanosine on intestinal inflammation in 2, 4-dinitrobenzene sulfonic acid (DNBS)-induced colitis in rats. Inflammopharmacology 27, 349–359 (2019).
Albrecht, P. et al. Extracellular cyclic GMP and its derivatives GMP and guanosine protect from oxidative glutamate toxicity. Neurochem. Int. 62, 610–619 (2013).
Dal-Cim, T. et al. Guanosine controls inflammatory pathways to afford neuroprotection of hippocampal slices under oxygen and glucose deprivation conditions. J. Neurochem. 126, 437–450 (2013).
Dal-Cim, T. et al. Guanosine protects human neuroblastoma SH-SY5Y cells against mitochondrial oxidative stress by inducing heme oxigenase-1 via PI3K/Akt/GSK-3beta pathway. Neurochem. Int. 61, 397–404 (2012).
Li, D. W. et al. Guanosine exerts neuroprotective effects by reversing mitochondrial dysfunction in a cellular model of Parkinson’s disease. Int. J. Mol. Med. 34, 1358–1364 (2014).
Marques, N. F., Massari, C. M. & Tasca, C. I. Guanosine protects striatal slices against 6-OHDA-induced oxidative damage, mitochondrial dysfunction, and ATP depletion. Neurotox. Res. 35, 475–483 (2019).
Nonose, Y. et al. Guanosine enhances glutamate uptake and oxidation, preventing oxidative stress in mouse hippocampal slices submitted to high glutamate levels. Brain Res. 1748, 147080 (2020).
Paniz, L. G. et al. Neuroprotective effects of guanosine administration on behavioral, brain activity, neurochemical and redox parameters in a rat model of chronic hepatic encephalopathy. Metab. Brain Dis. 29, 645–654 (2014).
Petronilho, F. et al. Protective effects of guanosine against sepsis-induced damage in rat brain and cognitive impairment. Brain Behav. Immun. 26, 904–910 (2012).
Quincozes-Santos, A. et al. Guanosine protects C6 astroglial cells against azide-induced oxidative damage: a putative role of heme oxygenase 1. J. Neurochem. 130, 61–74 (2014).
Tarozzi, A. et al. Guanosine protects human neuroblastoma cells from oxidative stress and toxicity induced by amyloid-beta peptide oligomers. J. Biol. Regul. Homeost. Agents 24, 297–306 (2010).
Thomaz, D. T. et al. Guanosine prevents nitroxidative stress and recovers mitochondrial membrane potential disruption in hippocampal slices subjected to oxygen/glucose deprivation. Purinergic Signal. 12, 707–718 (2016).
Dal-Cim, T. et al. Guanosine prevents oxidative damage and glutamate uptake impairment induced by oxygen/glucose deprivation in cortical astrocyte cultures: involvement of A1 and A2A adenosine receptors and PI3K, MEK, and PKC pathways. Purinergic Signal. 15, 465–476 (2019).
Decker, H. et al. Guanosine and GMP increase the number of granular cerebellar neurons in culture: dependence on adenosine A2A and ionotropic glutamate receptors. Purinergic Signal. 15, 439–450 (2019).
Nomiya, M., Andersson, K. E. & Yamaguchi, O. Chronic bladder ischemia and oxidative stress: new pharmacotherapeutic targets for lower urinary tract symptoms. Int. J. Urol. 22, 40–46 (2015).
Andersson, K. E., Fulhase, C., Soler, R. & Suimaraes-Souza, N. K. Update on uropharmacology: bladder dysfunction, nitric oxide, and reactive oxygen species. Curr. Bladder Dysfunct. Rep. 5, 150–156 (2010).
Liu, F. et al. Protective effects of inosine on urinary bladder function in rats with partial bladder outlet obstruction. Urology 73, 1417–1422 (2009).
Chung, Y. G. et al. Inosine Improves neurogenic detrusor overactivity following spinal cord injury. PLoS One 10, e0141492 (2015).
Chen, P., Goldberg, D. E., Kolb, B., Lanser, M. & Benowitz, L. I. Inosine induces axonal rewiring and improves behavioral outcome after stroke. Proc. Natl Acad. Sci. USA 99, 9031–9036 (2002).
Chang, R., Algird, A., Bau, C., Rathbone, M. P. & Jiang, S. Neuroprotective effects of guanosine on stroke models in vitro and in vivo. Neurosci. Lett. 431, 101–105 (2008).
Deng, G., Qiu, Z., Li, D., Fang, Y. & Zhang, S. Delayed administration of guanosine improves long-term functional recovery and enhances neurogenesis and angiogenesis in a mouse model of photothrombotic stroke. Mol. Med. Rep. 15, 3999–4004 (2017).
Ramos, D. B. et al. Intranasal guanosine administration presents a wide therapeutic time window to reduce brain damage induced by permanent ischemia in rats. Purinergic Signal. 12, 149–159 (2016).
Rathbone, M. P. et al. Systemic administration of guanosine promotes functional and histological improvement following an ischemic stroke in rats. Brain Res. 1407, 79–89 (2011).
Kelly, K. J., Plotkin, Z. & Dagher, P. C. Guanosine supplementation reduces apoptosis and protects renal function in the setting of ischemic injury. J. Clin. Invest. 108, 1291–1298 (2001).
Grunebaum, E., Cohen, A. & Roifman, C. M. Recent advances in understanding and managing adenosine deaminase and purine nucleoside phosphorylase deficiencies. Curr. Opin. Allergy Clin. Immunol. 13, 630–638 (2013).
Sasaki, Y. et al. Direct evidence of autosomal recessive inheritance of Arg24 to termination codon in purine nucleoside phosphorylase gene in a family with a severe combined immunodeficiency patient. Hum. Genet. 103, 81–85 (1998).
Grunebaum, E., Campbell, N., Leon-Ponte, M., Xu, X. & Chapdelaine, H. Partial purine nucleoside phosphorylase deficiency helps determine minimal activity required for immune and neurological development. Front. Immunol. 11, 1257 (2020).
Ohtani, N., Yamakoshi, K., Takahashi, A. & Hara, E. The p16INK4a-RB pathway: molecular link between cellular senescence and tumor suppression. J. Med. Invest. 51, 146–153 (2004).
Childs, B. G., Durik, M., Baker, D. J. & vanDeursen, J. M. Cellular senescence in aging and age-related disease from mechanisms to therapy. Nat. Med. 21, 1424–1435 (2015).
Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).
Birder, L. A. et al. A uro-protective agent with restorative actions on urethral and striated muscle morphology. World J. Urol. 39, 2685–2690 (2021).
Wickremaratchi, M. M. & Llewelyn, J. G. Effects of ageing on touch. Postgrad. Med. J. 82, 3910394 (2005).
Zalba, G. Oxidative stress in vascular pathophysiology: still much to learn. Antioxidants 10, 673 (2021).
Juan, Y. S. et al. Effect of ischemia/reperfusion on bladder nerve and detrusor cell damage. Int. Urol. Nephrol. 41, 513–521 (2009).
Pinggera, G. M. et al. Association of lower urinary tract symptoms and chronic ischaemia of the lower urinary tract in elderly women and men: assessment using colour Doppler ultrasonography. BJU Int. 102, 470–474 (2008).
Monk, B. A. & George, S. J. The effect of ageing on vascular smooth muscle cell behavior. Gerontology 61, 416–426 (2015).
Cheng, F. et al. Layer dependent role of collagen recruitment during loading of the rat bladder wall. Biomech. Model. Mechanobiol. 17, 403–417 (2018).
Tuttle, T. G., Lujan, H. L., Tykocki, N. R., DiCarlo, S. E. & Roccablanca, S. Remodeling of extracellular matrix in the urinary bladder of paraplegic rats results in increased compliance and delayed fiber recruitment 16 weeks after spinal cord injury. Acta Biomater. 141, 280–289 (2022).
Sebastian, D. Mfn2 deficiency links age-related sarcopenia and impaired autophagy to activation of an adaptive mitophagy pathway. EMBO J. 35, 1677–1682 (2016).
Frank, S., Gaume, B. & Bergmann-Leitner, E. W. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev. Cell 1, 515–525 (2001).
Rub, C., Wilkening, A. & Voos, W. Mitochondrial quality control by the Pink1/Parkin system. Cell Tissue Res. 367, 111–123 (2017).
Porter, A. G. & Janicke, R. U. Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 6, 99–110 (1999).
Chaitanya, G., Alexander, J. S. & Babu, P. PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration. Cell Commun. Signal. 8, 31 (2010).
Both authors are co-inventors on a (pending) patent, PCT/US2020/022697, which relates to the field of purine nucleoside phosphorylase (PNPase) inhibitors and PNPase purine nucleoside substrates for treating bladder and urethra dysfunction or disease.
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Birder, L.A., Jackson, E.K. Purine nucleoside phosphorylase as a target to treat age-associated lower urinary tract dysfunction. Nat Rev Urol 19, 681–687 (2022). https://doi.org/10.1038/s41585-022-00642-w