Mechanism of Action of Botulinum Neurotoxin and Overview of Medical Countermeasures for Intoxication

The botulinum neurotoxins (BoNTs)* comprise a family of seven distinct neurotoxic proteins (A-G) produced by immunologically discrete strains of the anaerobic bacterium Clostridium botulinum and in rare cases by Clostridium baratii and Clostridium butyricum (Habermann and Dreyer, 1986; Harvey et al., 2002; Simpson, 2004). These toxins act on peripheral cholinergic synapses to inhibit spontaneous and impulse-dependent release of acetylcholine (ACh) (Brooks, 1956; Kao et al., 1976). Intoxication by BoNT results in muscle weakness, which can be fatal when the diaphragm and intercostal muscles become sufficiently compromised to impair ventilation (Dickson and Shevky, 1923). The BoNTs are the most potent substances in nature, and exposure to as little as 1-3 ng/kg may be sufficient to cause human lethality (Gill, 1982; Middlebrook and Franz, 1997; Arnon et al., 2001). The purpose of this chapter is to use the insights gained in our understanding of the mechanism of BoNT action to establish a conceptual framework within which to develop effective treatment strategies for intoxication. The chapter is organized into three major topics: (l) an overview of BoNT action, (2) a description of the manifestations of botulism, and (3) an evaluation of conventional and emergent treatment options. Published in Chemical Warfare Agents: Chemistry, Pharmacology, Toxicology, and Therapeutics, chapter 16, 2nd edition, p389-422, 2008. ISBN 978-1-4200-4661-8 Editors: James A. Romano, Jr., Brian J. Lukey and Harry Salem