Getting muscles moving again after botulinum toxin: novel therapeutic challenges

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Abstract

The use of botulinum neurotoxins for the treatment of muscle hyperactivity and spasticity disorders has been remarkably successful, owing to the abilities of the toxins to elicit prolonged localized paralysis and the rarity of serious adverse effects. However, botulinum toxins are the most deadly protein toxins known, and existing antidotes possess limited effectiveness. Paradoxically, in situ, the intoxicated motoneuron does not die. It reacts by emanating a sprouting network known to implement new functional synapses, leading to resumption of neurotransmission. Recent studies have highlighted ways of accelerating this natural recovery process to overcome paralysis successfully. Developing new therapeutic strategies and treatments for botulism will require more research into the molecular understanding of this ‘naturally occurring’ recovery process.

Section snippets

Target and mode of intoxication

A precise molecular understanding of the series of events underlying BoNT-induced intoxication is required to design future effective treatments. The past decade has been rich in important discoveries in this field, including determining the sequences of BoNTs, identifying their zinc-endoprotease activity and molecular targets (reviewed in 1, 6), and establishing some of their crystal structures 8, 9.

BoNTs target cholinergic synapses of the peripheral nervous system: the neuromuscular junction (

Molecular basis of motoneuronal response to blockade of exocytosis: sprouting and terminal repair

When injected locally into humans for treatment, BoNT/A, B, C1, E and F cause neuromuscular paralysis for distinct periods of ∼4–6, 3, 4–5, 1 and 2 months, respectively [7]. The recovery times in rodents are shorter but show the same rank order 7, 19.

The dramatic reduction of the number of quanta being released per nerve impulse results in an endplate potential of insufficient amplitude to trigger muscle contraction, thus causing a flaccid paralysis 6, 10. Importantly, although the release of

Symptoms of poisoning

Worldwide, almost 1000 humans and many thousands of animals are afflicted annually 2, 3, 4, 5, 26. Botulism is manifested by a flaccid paralysis appearing initially in the head, neck and upper extremities, with ophthalmological dysfunction appearing first (blurred vision, ptosis and diplopia) [3]. Paralysis eventually spreads to the lower body and, in the most serious cases, paralysis of the diaphragm and intercostal muscles causes respiratory collapse 2, 3, 4, 26. When large toxin doses are

Novel therapies to prevent and rescue botulism

The exquisite lethality of BoNT (100 000× more toxic than Sarin nerve gas), together with its ability to poison by oral and inhalation routes, promotes these neurotoxins as agents for biological warfare 2, 3, 26. To reduce this threat, much effort has been devoted to the development of fast and effective treatments to counteract the effects of BoNTs (Fig. 4, Fig. 5).

Conclusions

Several major advances promise novel treatments in the near future to counteract the threat of poisoning by BoNTs. Recent significant progress in the understanding of BoNT intoxication have lead to serious concerns about the effectiveness of the current therapeutic strategies, both in terms of treatments for botulism and the clinical use of toxins for muscle overactivity disorders. One key issue raised is at what stage of the intoxication process is it safe to re-administer BoNT? Also, once

Acknowledgements

This paper is dedicated to my mentor, Dr Jordi Molgo, for successfully perpetuating the tradition of studying the cholinergic peripheral nervous system in France despite difficulties. We also wish to thank Joanna Westmoreland for her help in drawing most of the figures and Dr Shona Osborne for criticism and corrections.

References (44)

  • G.A. O'Sullivan

    Rescue of exocytosis in botulinum toxin A-poisoned chromaffin cells by expression of cleavage-resistant SNAP-25. Identification of the minimal essential C-terminal residues

    J. Biol. Chem.

    (1999)
  • J.E. Keller

    Persistence of botulinum neurotoxin action in cultured spinal cord cells

    FEBS Lett.

    (1999)
  • P.G. Foran

    Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E, and F compared with the long lasting type A. Basis for distinct durations of inhibition of exocytosis in central neurons

    J. Biol. Chem.

    (2003)
  • L.A. Broussard

    Biological agents: weapons of warfare and bioterrorism

    Mol. Diagn.

    (2001)
  • M.P. Byrne et al.

    Development of vaccines for prevention of botulism

    Biochimie

    (2000)
  • S. Foynes

    Vaccination against type F botulinum toxin using attenuated Salmonella enterica var Typhimurium strains expressing the BoNT/F H(C) fragment

    Vaccine

    (2003)
  • P. Amersdorfer

    Genetic and immunological comparison of anti-botulinum type A antibodies from immune and non-immune human phage libraries

    Vaccine

    (2002)
  • R. Eleopra

    Botulinum neurotoxin serotypes A and C do not affect motor units survival in humans: an electrophysiological study by motor units counting

    Clin. Neurophysiol.

    (2002)
  • M. Adler

    Persistence of botulinum neurotoxin A demonstrated by sequential administration of serotypes A and E in rat EDL muscle

    Toxicon

    (2001)
  • C.V. Jurasinski

    Correlation of cleavage of SNAP-25 with muscle function in a rat model of Botulinum neurotoxin type A induced paralysis

    Toxicon

    (2001)
  • J.J. Schmidt et al.

    A high-affinity competitive inhibitor of type A botulinum neurotoxin protease activity

    FEBS Lett.

    (2002)
  • M. Adler

    Efficacy of a novel metalloprotease inhibitor on botulinum neurotoxin B activity

    FEBS Lett.

    (1998)
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    These two authors contributed equally to the manuscript.

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