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Drug Insight: biological effects of botulinum toxin A in the lower urinary tract

Nature Clinical Practice Urology volume 5, pages 319–328 (2008)Cite this article

Abstract

Botulinum toxins can effectively and selectively disrupt and modulate neurotransmission in striated muscle. Recently, urologists have become interested in the use of these toxins in patients with detrusor overactivity and other urological disorders. In both striated and smooth muscle, botulinum toxin A (BTX-A) is internalized by presynaptic neurons after binding to an extracellular receptor (ganglioside and presumably synaptic vesicle protein 2C). In the neuronal cytosol, BTX-A disrupts fusion of the acetylcholine-containing vesicle with the neuronal wall by cleaving the SNAP-25 protein in the synaptic fusion complex. The net effect is selective paralysis of the low-grade contractions of the unstable detrusor, while still allowing high-grade contraction that initiates micturition. Additionally, BTX-A seems to have effects on afferent nerve activity by modulating the release of ATP in the urothelium, blocking the release of substance P, calcitonin gene-related peptide and glutamate from afferent nerves, and reducing levels of nerve growth factor. These effects on sensory feedback loops might not only help to explain the mechanism of BTX-A in relieving symptoms of overactive bladder, but also suggest a potential role for BTX-A in the relief of hyperalgesia associated with lower urinary tract disorders.

Key Points

  • There has been recent interest in the potential use of botulinum toxins, particularly botulinum toxin A (BTX-A), in patients with detrusor overactivity and other urological disorders

  • After internalization of BTX-A into the cytosol of presynaptic neurons, it disrupts fusion of the acetylcholine-containing vesicle with the neuronal wall by cleaving the SNAP-25 protein in the synaptic fusion complex

  • In detrusor overactivity, the effect of BTX-A results in selective paralysis of the low-grade contractions of the unstable detrusor, while still allowing the high-grade contractions that initiate micturition

  • BTX-A also seems to affect afferent nerve activity by modulating the release of ATP in the urothelium, blocking the release of substance P, calcitonin gene-related peptide and glutamate from afferent nerves, and reducing the levels of nerve growth factor

  • In view of its effects on sensory feedback loops, BTX-A could have a potential role in relieving hyperalgesia associated with lower urinary tract disorders, in addition to its reported beneficial effects on symptoms of overactive bladder

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Figure 1: Structure of BTX-A.
Figure 2: Internalization and translocation of BTX-A.
Figure 3: Inhibition of acetylcholine exocytosis by BTX-A.

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Acknowledgements

Natalie Avenell-Mills provided research and editorial assistance for the development of the manuscript, with support from Allergan, Inc.

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Authors and Affiliations

  1. MB Chancellor is Director of the Neurourology Program in the Department of Urology at the William Beaumont Hospital in Royal Oak, MI, USA.,

    Michael B Chancellor

  2. CJ Fowler is Professor of Uroneurology at the National Hospital of Neurology & Neurosurgery in Queen Square, London, UK.,

    Clare J Fowler

  3. A Apostolidis is a Consultant Urologist and a Lecturer in Neurourology at the 2nd Department of Urology at the Aristotle University of Thessaloniki, Greece.,

    Apostolos Apostolidis

  4. WC de Groat is a Professor of Pharmacology at the University of Pittsburgh School of Medicine in Pittsburgh, PA, USA.,

    William C de Groat

  5. CP Smith is an Assistant Professor in the Scott Department of Urology and GT Somogyi is Director of the Scott Department of Urology, Neurourology Laboratory and a Professor in the Scott Department of Urology at the Baylor College of Medicine, Houston, TX, USA.,

    Christopher P Smith & George T Somogyi

  6. KR Aoki is the Vice President and Neurotoxin Research Team Leader in the Biological Sciences Department at Allergan, Inc.,

    K Roger Aoki

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  1. Michael B Chancellor
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Correspondence to Michael B Chancellor.

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Competing interests

MB Chancellor is a consultant for Allergan, Inc. and has received grant/research support from Allergan, Inc. CJ Fowler is a consultant and speaker for Allergan Inc., and has also received grant/research support from the company. A Apostolidis is a consultant for Allergan Inc., and has also received grant/research support from the company. WC de Groat is a consultant for Allergan Inc. CP Smith is a consultant for Allergan Inc. and has received grant/research support from the company. GT Somogyi has received grant/research support from Allergan Inc., and KR Aoki is a stockholder/director of Allergan Inc.

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Chancellor, M., Fowler, C., Apostolidis, A. et al. Drug Insight: biological effects of botulinum toxin A in the lower urinary tract. Nat Rev Urol 5, 319–328 (2008). https://doi.org/10.1038/ncpuro1124

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