Trends in Molecular Medicine
Getting muscles moving again after botulinum toxin: novel therapeutic challenges
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.
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These two authors contributed equally to the manuscript.