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2 - Mechanistic basis for the therapeutic effectiveness of botulinum toxin A on over-active cholinergic nerves

Published online by Cambridge University Press:  02 December 2009

By
J. Oliver Dolly  and
Gary Lawrence
Edited by
Anthony B. Ward  and
Michael P. Barnes
J. Oliver Dolly
Affiliation:
International Centre for Neurotherapeutics, Dublin City University, Dublin, Ireland
Gary Lawrence
Affiliation:
International Centre for Neurotherapeutics, Dublin City University, Dublin, Ireland
Anthony B. Ward
Affiliation:
University Hospital of North Staffordshire
Michael P. Barnes
Affiliation:
Hunters Moor Regional Neurological Rehabilitation Centre
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Summary

Introduction

Seven homologous variants (serotypes A–G) of botulinum neurotoxin (BoNT) are produced by different Clostridium botulinum, and closely-related toxins have been isolated from C. butyricum and C. barati. All are proteins with Mr ∼ 150 K which are activated by selective proteolytic cleavage to yield a heavy chain (HC) and a light chain (LC) linked by a disulphide bond and non-covalent interactions. Each exhibits amazingly high specific neurotoxicities (107–108 mouse LD50 units/mg) after separation from their naturally-occurring complexes with accessory proteins. The size and composition of such complexes differ for each serotype; for example, type A can be isolated as large assemblies (LL or L forms with Mr ∼ 900 or 450 K) of the active moiety, BoNT, with non-toxic non-haemagglutinin and several haemagglutinin proteins.

Long before the recent spiralling interest worldwide in type A toxin as a therapeutic for weakening hyper-active muscles, BoNTs had been adopted as informative probes. for delineating the fundamental process of quantal transmitter release. This choice was based on their renowned abilities to induce neuromuscular paralysis by presynaptic inhibition of acetylcholine (ACh) release. with exquisite specificity (i.e. without affecting any other measured parameters such as ion channels in the nerve terminal, ACh synthesis, etc.). Also, other toxins had been shown to be useful for the biochemical characterization of neurotransmitter receptors and cation channels. Another attraction of using BoNTs was that motor nerves in frog paralysed with type D did not atrophy or undergo any detectable ultrastructural changes over ∼50 days; likewise, mammalian nerve endings treated with type A did not degenerate but, instead, underwent remodelling that culminated in full recovery of neuro-exocytosis after 90 days.

Type
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Information
Clinical Uses of Botulinum Toxins , pp. 9 - 26
Publisher: Cambridge University Press
Print publication year: 2007

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