Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Neurotrophins as regulators of urinary bladder function

Nature Reviews Urology volume 9, pages 628–637 (2012)Cite this article

Subjects

Abstract

Increased voiding frequency and urgency are among the most prevalent storage lower urinary tract symptoms (LUTS), often diagnosed as part of overactive bladder syndrome (OAB). It has been suggested that these symptoms are caused by excessive sensory activation of the neural micturition circuit. It seems likely that sensory pathway remodelling is also responsible for pain perception upon bladder filling in patients with bladder pain syndrome (BPS). Neurotrophins—including nerve growth factor (NGF), brain-derived nerve factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4)—represent master modulators of neural plasticity, both in peripheral and central nervous systems. Accumulating evidence points towards a role for neurotrophins in the control of neural sensory function during micturition and indicates their involvement in the emergence of OAB-related and BPS-related LUTS. Neurotrophins could potentially be used as urinary biomarkers to improve diagnostic accuracy for OAB and BPS and monitor therapy effectiveness. Proof-of-principle clinical evidence has confirmed that NGF is a potential target for treating human bladder overactivity.

Key Points

  • Urgency, frequency and bladder pain are all associated with hypersensitization and remodelling of bladder peripheral afferents

  • Exogenous administration of nerve growth factor (NGF) to the bladder or spinal cord induces bladder overactivity in experimental animal models

  • NGF—and possibly brain-derived neurotrophic factor (BDNF)—is produced in the bladder by urothelium and smooth muscle cells upon stretch and inflammation to sensitize underlying bladder afferent C fibres

  • Peripheral or central NGF sequestration reduces bladder overactivity in experimental models of spinal cord injury, bladder inflammation and outlet obstruction; local NGF delivery improves bladder underactivity in experimental diabetic cystopathy

  • NGF and BDNF represent potential disease biomarkers for bladder pain syndrome/interstitial cystitis (BPS/IC) and overactive bladder syndrome; increased urinary excretion correlates with symptom severity and can be modulated by therapy

  • Neurotrophin system intervention using the monoclonal NGF antibody tanezumab has been shown to improve self-reported bladder pain scores and urgency episode frequency in patients with BPS/IC

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Peripheral mechanisms involved in the neurotrophin-mediated development of bladder overactivity.
Figure 2: Central mechanisms involved in the neurotrophin-mediated development of bladder overactivity.

Similar content being viewed by others

References

  1. Fowler, C. J., Griffiths, D. & de Groat, W. C. The neural control of micturition. Nat. Rev. Neurosci. 9, 453–466 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hashim, H. & Abrams, P. Overactive bladder: an update. Curr. Opin. Urol. 17, 231–236 (2007).

    Article  PubMed  Google Scholar 

  3. Abrams, P. et al. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology 61, 37–49 (2003).

    Article  PubMed  Google Scholar 

  4. de Groat, W. C. & Yoshimura, N. Afferent nerve regulation of bladder function in health and disease. Handb. Exp. Pharmacol. 194, 91–138 (2009).

    Article  CAS  Google Scholar 

  5. Kanai, A. & Andersson, K. E. Bladder afferent signaling: recent findings. J. Urol. 183, 1288–1295 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fall, M., Oberpenning, F. & Peeker, R. Treatment of bladder pain syndrome/interstitial cystitis can we make evidence-based decisions? Eur. Urol. 54, 65–75 (2008).

    Article  PubMed  Google Scholar 

  7. Hanno, P. et al. Bladder Pain Syndrome Committee of the International Consultation on Incontinence. Neurourol. Urodyn. 29, 191–198 (2010).

    Article  PubMed  Google Scholar 

  8. Wiseman, O. J. et al. The ultrastructure of bladder lamina propria nerves in healthy subjects and patients with detrusor hyperreflexia. J. Urol. 168, 2040–2045 (2002).

    Article  PubMed  Google Scholar 

  9. Apodaca, G., Balestreire, E. & Birder, L. A. The uroepithelial-associated sensory web. Kidney Int. 72, 1057–1064 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Birder, L. A. & de Groat, W. C. Mechanisms of disease: involvement of the urothelium in bladder dysfunction. Nat. Clin. Pract. Urol. 4, 46–54 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pezet, S. & McMahon, S. B. Neurotrophins: mediators and modulators of pain. Ann. Rev. Neurosci. 29, 507–538 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Andersson, K. E. Detrusor myocyte activity and afferent signaling. Neurourol. Urodyn. 29, 97–106 (2010).

    Article  PubMed  Google Scholar 

  13. Gillespie, J. I., van Koeveringe, G. A., de Wachter, S. G. & de Vente, J. On the origins of the sensory output from the bladder: the concept of afferent noise. BJU Int. 103, 1324–1333 (2009).

    Article  PubMed  Google Scholar 

  14. Kawakami, T., Wakabayashi, Y., Isono, T., Aimi, Y. & Okada, Y. Expression of neurotrophin messenger RNAs during rat urinary bladder development. Neurosci. Lett. 329, 77–80 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Vizzard, M. A., Wu, K. H. & Jewett, I. T. Developmental expression of urinary bladder neurotrophic factor mRNA and protein in the neonatal rat. Brain Res. Dev. Brain Res. 119, 217–224 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Levi-Montalcini, R. & Hamburger, V. Selective growth stimulating effects of mouse sarcoma on the sensory and sympathetic nervous system of the chick embryo. J. Exp. Zool. 116, 321–361 (1951).

    Article  CAS  PubMed  Google Scholar 

  17. Levi-Montalcini, R. The nerve growth factor 35 years later. Science 237, 1154–1162 (1987).

    Article  CAS  PubMed  Google Scholar 

  18. Ernsberger, U. Role of neurotrophin signalling in the differentiation of neurons from dorsal root ganglia and sympathetic ganglia. Cell Tissue Res. 336, 349–384 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Tuttle, J. B. & Steers, W. D. Nerve growth factor responsiveness of cultured major pelvic ganglion neurons from the adult rat. Brain Res. 588, 29–40 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Schnegelsberg, B. et al. Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R534–R547 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Skaper, S. D., Pollock, M. & Facci, L. Mast cells differentially express and release active high molecular weight neurotrophins. Brain Res. Mol. Brain Res. 97, 177–185 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Skaper, S. D. Nerve growth factor: a neurokine orchestrating neuroimmune-endocrine functions. Mol. Neurobiol. 24, 183–199 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Jang, J., Park, E. Y., Seo, S. I., Hwang, T. K. & Kim, J. C. Effects of intravesical instillation of cyclooxygenase-2 inhibitor on the expression of inducible nitric oxide synthase and nerve growth factor in cyclophosphamide-induced overactive bladder. BJU Int. 98, 435–439 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Gonzalez, R. R. et al. Modulating bladder neuro-inflammation: RDP58, a novel anti-inflammatory peptide, decreases inflammation and nerve growth factor production in experimental cystitis. J. Urol. 173, 630–634 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Meyer-Siegler, K. L. & Vera, P. L. Substance P induced release of macrophage migration inhibitory factor from rat bladder epithelium. J. Urol. 171, 1698–1703 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Dupont, M. C., Spitsbergen, J. M., Kim, K. B., Tuttle, J. B. & Steers, W. D. Histological and neurotrophic changes triggered by varying models of bladder inflammation. J. Urol. 166, 1111–1118 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Mantyh, P. W., Koltzenburg, M., Mendell, L. M., Tive, L. & Shelton, D. L. Antagonism of nerve growth factor-TrkA signaling and the relief of pain. Anesthesiology 115, 189–204 (2011).

    Article  PubMed  Google Scholar 

  28. Apfel, S. C. et al. Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: a randomized controlled trial. rhNGF Clinical Investigator Group. JAMA 284, 2215–2221 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Thoenen, H. & Sendtner, M. Neurotrophins: from enthusiastic expectations through sobering experiences to rational therapeutic approaches. Nat. Neurosci. 5, 1046–1050 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Steers, W. D. & Tuttle, J. B. Mechanisms of Disease: the role of nerve growth factor in the pathophysiology of bladder disorders. Nat. Clin. Pract. Urol. 3, 101–110 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Dmitrieva, N. & McMahon, S. B. Sensitisation of visceral afferents by nerve growth factor in the adult rat. Pain 66, 87–97 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Dmitrieva, N., Shelton, D., Rice, A. S. & McMahon, S. B. The role of nerve growth factor in a model of visceral inflammation. Neuroscience 78, 449–459 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Zvara, P. & Vizzard, M. A. Exogenous overexpression of nerve growth factor in the urinary bladder produces bladder overactivity and altered micturition circuitry in the lumbosacral spinal cord. BMC Physiol. 7, 9 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yoshimura, N. et al. Bladder overactivity and hyperexcitability of bladder afferent neurons after intrathecal delivery of nerve growth factor in rats. J. Neurosci. 26, 10847–10855 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Frias, B. et al. TRPV1 mediates NGF-induced bladder overactivity and noxious input. BJU Int. http://dx.doi.org/10.1111/j.1464-410X.2012.11187.x

  36. Winston, J., Toma, H., Shenoy, M. & Pasricha, P. J. Nerve growth factor regulates VR-1 mRNA levels in cultures of adult dorsal root ganglion neurons. Pain 89, 181–186 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Zhuang, Z. Y., Xu, H., Clapham, D. E. & Ji, R. R. Phosphatidylinositol 3-kinase activates ERK in primary sensory neurons and mediates inflammatory heat hyperalgesia through TRPV1 sensitization. J. Neurosci. 24, 8300–8309 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Charrua, A. et al. Functional transient receptor potential vanilloid 1 is expressed in human urothelial cells. J. Urol. 182, 2944–2950 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Snider, W. D. Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77, 627–638 (1994).

    Article  PubMed  Google Scholar 

  40. Song, X. Y., Li, F., Zhang, F. H., Zhong, J. H. & Zhou, X. F. Peripherally-derived BDNF promotes regeneration of ascending sensory neurons after spinal cord injury. PLoS ONE 3, e1707 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Girard, B. M., Malley, S. E. & Vizzard, M. A. Neurotrophin/receptor expression in urinary bladder of mice with overexpression of NGF in urothelium. Am. J. Physiol. Renal Physiol. 300, F345–F355 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Pinto, R. et al. Sequestration of brain derived nerve factor by intravenous delivery of TrkB-Ig2 reduces bladder overactivity and noxious input in animals with chronic cystitis. Neuroscience 166, 907–916 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Vizzard, M. A. Changes in urinary bladder neurotrophic factor mRNA and NGF protein following urinary bladder dysfunction. Exp. Neurol. 161, 273–284 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Pezet, S., Malcangio, M. & McMahon, S. B. BDNF: a neuromodulator in nociceptive pathways? Brain Res. Rev. 40, 240–249 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Michael, G. J. et al. Nerve growth factor treatment increases brain-derived neurotrophic factor selectively in TrkA-expressing dorsal root ganglion cells and in their central terminations within the spinal cord. J. Neurosci. 17, 8476–8490 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Moutzouris, D. A. & Falagas, M. E. Interstitial cystitis: an unsolved enigma. Clin. J. Am. Soc. Nephrol. 4, 1844–1857 (2009).

    Article  PubMed  Google Scholar 

  47. Hanno, P. M. et al. AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. J. Urol. 185, 2162–2170 (2011).

    Article  PubMed  Google Scholar 

  48. Berry, S. H. et al. Prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the United States. J. Urol. 186, 540–544 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Liu, H. T. & Kuo, H. C. Intravesical botulinum toxin A injections plus hydrodistension can reduce nerve growth factor production and control bladder pain in interstitial cystitis. Urology 70, 463–468 (2007).

    Article  PubMed  Google Scholar 

  50. Pinto, R. et al. Trigonal injection of botulinum toxin A in patients with refractory bladder pain syndrome/interstitial cystitis. Eur. Urol. 58, 360–365 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Christmas, T. J., Rode, J., Chapple, C. R., Milroy, E. J. & Turner-Warwick, R. T. Nerve fibre proliferation in interstitial cystitis. Virchows Arch. A Pathol. Anat. Histopathol. 416, 447–451 (1990).

    Article  CAS  PubMed  Google Scholar 

  52. Christmas, T. J. & Rode, J. Characteristics of mast cells in normal bladder, bacterial cystitis and interstitial cystitis. Br. J. Urol. 68, 473–478 (1991).

    Article  CAS  PubMed  Google Scholar 

  53. Birder, L. A., Hanna-Mitchell, A. T., Mayer, E. & Buffington, C. A. Cystitis, co-morbid disorders and associated epithelial dysfunction. Neurourol. Urodyn. 30, 668–672 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Chai, T. C. & Keay, S. New theories in interstitial cystitis. Nat. Clin. Pract. Urol. 1, 85–89 (2004).

    Article  PubMed  Google Scholar 

  55. Lowe, E. M. et al. Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis. Br. J. Urol. 79, 572–577 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Chancellor, M. B. et al. Drug Insight: biological effects of botulinum toxin A in the lower urinary tract. Nat. Clin. Pract. Urol. 5, 319–328 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Liu, H. T., Tyagi, P., Chancellor, M. B. & Kuo, H. C. Urinary nerve growth factor level is increased in patients with interstitial cystitis/bladder pain syndrome and decreased in responders to treatment. BJU Int. 104, 1476–1481 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Pinto, R. et al. Trigonal injection of botulinum toxin A in patients with refractory bladder pain syndrome/interstitial cystitis. Eur. Urol. 58, 360–365 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Tyagi, P. et al. Intravesical antisense therapy for cystitis using TAT-peptide nucleic acid conjugates. Mol. Pharm. 3, 398–406 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Frias, B. et al. Intrathecal blockade of Trk receptor and neurotrophins sequestration reduces pain and urinary frequency in an animal model of chronic bladder inflammation. Neurourol. Urodyn. 28, 708 (2009).

    Google Scholar 

  61. Hu, V. Y. et al. Decrease in bladder overactivity with REN1820 in rats with cyclophosphamide induced cystitis. J. Urol. 173, 1016–1021 (2005).

    Article  PubMed  Google Scholar 

  62. Evans, R. J. et al. Proof of concept trial of tanezumab for the treatment of symptoms associated with interstitial cystitis. J. Urol. 185, 1716–1721 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  64. Wood, J. N. Nerve growth factor and pain. N. Engl. J. Med. 363, 1572–1573 (2010).

    Article  PubMed  Google Scholar 

  65. de Groat, W. C. & Yoshimura, N. Plasticity in reflex pathways to the lower urinary tract following spinal cord injury. Exp. Neurol. 235, 123–132 (2012).

    Article  PubMed  Google Scholar 

  66. Kalsi, V. & Fowler, C. J. Therapy Insight: bladder dysfunction associated with multiple sclerosis. Nat. Clin. Pract. Urol. 2, 492–501 (2005).

    Article  PubMed  Google Scholar 

  67. Apostolidis, A. et al. Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity. J. Urol. 174, 977–982 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Liu, H. T., Chancellor, M. B. & Kuo, H. C. Urinary nerve growth factor levels are elevated in patients with detrusor overactivity and decreased in responders to detrusor botulinum toxin-A injection. Eur. Urol. 56, 700–706 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Giannantoni, A. et al. Botulinum-A toxin injections into the detrusor muscle decrease nerve growth factor bladder tissue levels in patients with neurogenic detrusor overactivity. J. Urol. 175, 2341–2344 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Zvarova, K., Murray, E. & Vizzard, M. A. Changes in galanin immunoreactivity in rat lumbosacral spinal cord and dorsal root ganglia after spinal cord injury. J. Comp. Neurol. 475, 590–603 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Persson, K., Steers, W. D. & Tuttle, J. B. Regulation of nerve growth factor secretion in smooth muscle cells cultured from rat bladder body, base and urethra. J. Urol. 157, 2000–2006 (1997).

    Article  CAS  PubMed  Google Scholar 

  72. Tanner, R., Chambers, P., Khadra, M. H. & Gillespie, J. I. The production of nerve growth factor by human bladder smooth muscle cells in vivo and in vitro. BJU Int. 85, 1115–1119 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Ramer, M. S., Bradbury, E. J. & McMahon, S. B. Nerve growth factor induces P2X(3) expression in sensory neurons. J. Neurochem. 77, 864–875 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Seki, S. et al. Immunoneutralization of nerve growth factor in lumbosacral spinal cord reduces bladder hyperreflexia in spinal cord injured rats. J. Urol. 168, 2269–2274 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Seki, S. et al. Suppression of detrusor-sphincter dyssynergia by immunoneutralization of nerve growth factor in lumbosacral spinal cord in spinal cord injured rats. J. Urol. 171, 478–482 (2004).

    Article  PubMed  Google Scholar 

  76. Mirone, V., Imbimbo, C., Longo, N. & Fusco, F. The detrusor muscle: an innocent victim of bladder outlet obstruction. Eur. Urol. 51, 57–66 (2007).

    Article  PubMed  Google Scholar 

  77. Steers, W. D., Kolbeck, S., Creedon, D. & Tuttle, J. B. Nerve growth factor in the urinary bladder of the adult regulates neuronal form and function. J. Clin. Invest. 88, 1709–1715 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Steers, W. D., Creedon, D. J. & Tuttle, J. B. Immunity to nerve growth factor prevents afferent plasticity following urinary bladder hypertrophy. J. Urol. 155, 379–385 (1996).

    Article  CAS  PubMed  Google Scholar 

  79. Liu, H. T. & Kuo, H. C. Urinary nerve growth factor levels are increased in patients with bladder outlet obstruction with overactive bladder symptoms and reduced after successful medical treatment. Urology 72, 104–108 (2008).

    Article  PubMed  Google Scholar 

  80. Kim, J. C. et al. Changes of urinary nerve growth factor and prostaglandins in male patients with overactive bladder symptom. Int. J. Urol. 12, 875–880 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Yokoyama, T., Kumon, H. & Nagai, A. Correlation of urinary nerve growth factor level with pathogenesis of overactive bladder. Neurourol. Urodyn. 27, 417–420 (2008).

    Article  PubMed  Google Scholar 

  82. Kim, J. C., Kim, D. B., Seo, S. I., Park, Y. H. & Hwang, T. K. Nerve growth factor and vanilloid receptor expression, and detrusor instability, after relieving bladder outlet obstruction in rats. BJU Int. 94, 915–918 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Persson, K., Sando, J. J., Tuttle, J. B. & Steers, W. D. Protein kinase C in cyclic stretch-induced nerve growth factor production by urinary tract smooth muscle cells. Am. J. Physiol. 269, C1018–C1024 (1995).

    Article  CAS  PubMed  Google Scholar 

  84. Araki, I. et al. Overexpression of epithelial sodium channels in epithelium of human urinary bladder with outlet obstruction. Urology 64, 1255–1260 (2004).

    Article  PubMed  Google Scholar 

  85. Kim, J. C., Park, E. Y., Seo, S. I., Park, Y. H. & Hwang, T. K. Nerve growth factor and prostaglandins in the urine of female patients with overactive bladder. J. Urol. 175, 1773–1776 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Liu, H. T. & Kuo, H. C. Urinary nerve growth factor levels are elevated in patients with overactive bladder and do not significantly increase with bladder distention. Neurourol. Urodyn. 28, 78–81 (2009).

    Article  PubMed  Google Scholar 

  87. Liu, H. T. & Kuo, H. C. Urinary nerve growth factor level could be a potential biomarker for diagnosis of overactive bladder. J. Urol. 179, 2270–2274 (2008).

    Article  PubMed  Google Scholar 

  88. Birder, L. A., Wolf-Johnston, A., Griffiths, D. & Resnick, N. M. Role of urothelial nerve growth factor in human bladder function. Neurourol. Urodyn. 26, 405–409 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Liu, H. T., Lin, H. & Kuo, H. C. Increased serum nerve growth factor levels in patients with overactive bladder syndrome refractory to antimuscarinic therapy. Neurourol. Urodyn. 30, 1525–1529 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Liu, H. T., Chancellor, M. B. & Kuo, H. C. Decrease of urinary nerve growth factor levels after antimuscarinic therapy in patients with overactive bladder. BJU Int. 103, 1668–1672 (2009).

    Article  CAS  PubMed  Google Scholar 

  91. Kuo, H. C., Liu, H. T. & Chancellor, M. B. Urinary nerve growth factor is a better biomarker than detrusor wall thickness for the assessment of overactive bladder with incontinence. Neurourol. Urodyn. 29, 482–487 (2010).

    PubMed  Google Scholar 

  92. Kebapci, N., Yenilmez, A., Efe, B., Entok, E. & Demirustu, C. Bladder dysfunction in type 2 diabetic patients. Neurourol. Urodyn. 26, 814–819 (2007).

    Article  PubMed  Google Scholar 

  93. Lee, W. C., Wu, H. P., Tai, T. Y., Yu, H. J. & Chiang, P. H. Investigation of urodynamic characteristics and bladder sensory function in the early stages of diabetic bladder dysfunction in women with type 2 diabetes. J. Urol. 181, 198–203 (2009).

    Article  PubMed  Google Scholar 

  94. Daneshgari, F., Liu, G., Birder, L., Hanna-Mitchell, A. T. & Chacko, S. Diabetic bladder dysfunction: current translational knowledge. J. Urol. 182, S18–S26 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Steinbacher, B. C. Jr & Nadelhaft, I. Increased levels of nerve growth factor in the urinary bladder and hypertrophy of dorsal root ganglion neurons in the diabetic rat. Brain Res. 782, 255–260 (1998).

    Article  CAS  PubMed  Google Scholar 

  96. Sasaki, K. et al. Diabetic cystopathy correlates with a long-term decrease in nerve growth factor levels in the bladder and lumbosacral dorsal root ganglia. J. Urol. 168, 1259–1264 (2002).

    Article  PubMed  Google Scholar 

  97. Tomlinson, D. R., Fernyhough, P. & Diemel, L. T. Role of neurotrophins in diabetic neuropathy and treatment with nerve growth factors. Diabetes 46, S43–S49 (1997).

    Article  CAS  PubMed  Google Scholar 

  98. Anand, P. et al. The role of endogenous nerve growth factor in human diabetic neuropathy. Nat. Med. 2, 703–707 (1996).

    Article  CAS  PubMed  Google Scholar 

  99. Sasaki, K. et al. Gene therapy using replication-defective herpes simplex virus vectors expressing nerve growth factor in a rat model of diabetic cystopathy. Diabetes 53, 2723–2730 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Liu, H. T., Chancellor, M. B. & Kuo, H. C. Urinary nerve growth factor level could be a biomarker in the differential diagnosis of mixed urinary incontinence in women. BJU Int. 102, 1440–1444 (2008).

    PubMed  Google Scholar 

  101. Kuo, H. C., Liu, H. T. & Chancellor, M. B. Can urinary nerve growth factor be a biomarker for overactive bladder? Rev. Urol. 12, e69–e77 (2010).

    PubMed  PubMed Central  Google Scholar 

  102. Antunes-Lopes, T., Carvalho-Barros, S., Cruz, C. D., Cruz, F. & Martins-Silva, C. Biomarkers in overactive bladder: a new objective and noninvasive tool? Adv. Urol. 382431 (2011).

  103. Antunes-Lopes, T. et al. Urinary levels of brain derived neurotrophic factor (BDNF) in women with overactive bladder (OAB) syndrome correlate with the severity of symptoms. Eur. Urol. 10, 277–278 (2011).

    Article  Google Scholar 

  104. Okragly, A. J. et al. Elevated tryptase, nerve growth factor, neurotrophin-3 and glial cell line-derived neurotrophic factor levels in the urine of interstitial cystitis and bladder cancer patients. J. Urol. 161, 438–441 (1999).

    Article  CAS  PubMed  Google Scholar 

  105. US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  106. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  107. US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  108. Lane, N. E. et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N. Engl. J. Med. 363, 1521–1531 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Holmes, D. Anti-NGF painkillers back on track? Nat. Rev. Drug Discov. 11, 337–338 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Apostolidis, A. et al. Recommendations on the use of botulinum toxin in the treatment of lower urinary tract disorders and pelvic floor dysfunctions: a European consensus report. Eur. Urol. 55, 100–119 (2009).

    Article  CAS  PubMed  Google Scholar 

  111. Chuang, Y. C., Lee, W. C., Lee, W. C. & Chiang, P. H. Intravesical liposome versus oral pentosan polysulfate for interstitial cystitis/painful bladder syndrome. J. Urol. 182, 1393–1400 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Eibl, J. K., Chapelsky, S. A. & Ross, G. M. Multipotent neurotrophin antagonist targets brain-derived neurotrophic factor and nerve growth factor. J. Pharmacol. Exp. Ther. 332, 446–454 (2010).

    Article  CAS  PubMed  Google Scholar 

  113. Hefti, F. F. et al. Novel class of pain drugs based on antagonism of, N. G. F. Trends Pharmacol. Sci. 27, 85–91 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Work in the laboratories of P. Ochodnicky, C. D. Cruz and F. Cruz is supported by the European Community's FP7, HEALTH-F2-2008-223234 InComb grant. Work in the laboratory of N. Yoshimura is supported by the National Institutes of Health (DK057267 and DK088836) and the United States Department of Defense (SC100134 and PR110326). The authors thank Martin C. Michel for his inspiration and help during the preparation of this manuscript.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Pharmacotherapy, Academic Medical Center, University of Amsterdam, Meibergdreef 15, Amsterdam, 1105, AZ, The Netherlands

    Peter Ochodnicky

  2. Department of Experimental Biology, Faculty of Medicine and IBMC Institute of Molecular Cell Biology. University of Porto, Alameda Hernâni Monteiro, Porto, 4200-319, Portugal

    Célia D. Cruz & Francisco Cruz

  3. Department of Urology, University of Pittsburgh School of Medicine, Suite 700, Kaufmann Medical Building, 3471 Fifth Avenue, Pittsburgh, 15213, PA, USA

    Naoki Yoshimura

Authors
  1. Peter Ochodnicky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Célia D. Cruz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Naoki Yoshimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francisco Cruz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

P. Ochodnicky researched data for the article. C. Cruz and P. Ochodnicky wrote the article. All authors contributed towards discussions of content, in addition to reviewing and editing the manuscript prior to submission.

Corresponding author

Correspondence to Peter Ochodnicky.

Ethics declarations

Competing interests

Peter Ochodnicky, Celia Cruz and Naoki Yoshimura declare no competing interests. Francisco Cruz has provided consultancy, received honoraria and research support from Allergan, Astellas, Recordati and received speakers honoraria from AMS and Pfizer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ochodnicky, P., Cruz, C., Yoshimura, N. et al. Neurotrophins as regulators of urinary bladder function. Nat Rev Urol 9, 628–637 (2012). https://doi.org/10.1038/nrurol.2012.178

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrurol.2012.178

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research