Page 784 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

VetBooks.ir Chapter 55

Botulinum Neurotoxins

Rhian B. Cope

INTRODUCTION BACTERIAL SYNTHESIS

Botulinum toxins are exotoxins produced by Clostridium Botulinum toxins are synthesized as a 150 kD progenitor
botulinum; a Gram-positive anaerobic rod shaped bacte- toxin that is then cleaved to form an active dimer consist-
rium, and related Clostridia including C. butyricum, ing of disulphide bond linked heavy and light chains
C. baratii,and C. argentinense (Popoff and Bouvet, 2013; (Fig. 55.1). When isolated from Clostridia, botulinum
Pirazzini et al., 2017). Thesetoxinsare afamily of toxins are found in 300 500 kD complexes with hemag-
structurally similar, but antigenically and serologically glutinins and other nonhemagglutinin, nontoxic proteins.
distinct, neurotoxins that consist of two basic components:
the neurotoxic component (light chain) and the accessory
MECHANISM OF ACTION
component (heavy chain). There are now eight antigenically
distinct toxin serotypes (A,B, C1,C2,D,E,F, G, H; The overall classical mode of action is to presynaptically
Barash and Arnon, 2014; Dover et al., 2014). Human botu- bind to high-affinity recognition sites on the cholinergic
lismismostlycausedbyserotypesA,B,E andFwhileser- nerve terminals, decrease the release of acetylcholine, and
otypes C and D only cause toxicity in animals. Serotype H produce presynaptic neuromuscular blockade. Denervation
was recently discovered in the feces of a child suffering bot- muscular atrophy accompanies the neuromuscular block-
ulism (Barash and Arnon, 2014). Six of the serotypes have ade. Although effected neuromuscular junctions may even-
additional subtypes (Dover et al., 2014; Kalb et al., 2011). tually recover, most of the recovery from botulinum toxin
Botulinum toxin A and B have been successfully com- neuromuscular blockade results from proximal axonal
mercialized as pharmaceuticals for the treatment of cervi- sprouting and muscle reinnervation through the synthesis
cal dystonia, severe primary axillary hyperhidrosis, of new neuromuscular junctions (de Paiva et al., 1999).
strabismus, blepharospasm, neurogenic detrusor over The terminal membrane acceptor-binding domain (H c )
activity, chronic migraine, upper limb spasticity, lateral and N-terminal translocation domains on the toxin heavy
canthal lines (crow’s feet) and glabellar lines. Critically, chain facilitate the translocation of the light chain into the
serious medication errors have occurred with different neuronal cytosol via a pH dependent mechanism. Within
types of pharmaceutical botulinum toxins due to their dif- the nerve terminal cytosol, the light chain polypeptide is
ferent individual potencies. separated from the heavy chain and refolded to form a
Botulinum toxin A is a noted potential bioweapon. An Zn 21 metalloprotease. The light chain metalloproteases
estimated 1 g of botulinum toxin A could kill more than one have different cellular targets in the sequence of events
million people via inhalation exposure (the preferred expo- leading to the release of acetylcholine in to the synaptic
sure pathway for weaponization; Arnon et al., 2001a,b). cleft depending on the toxin serotype (Table 55.1,
The estimated median IV lethal dose of botulinum toxin Fig. 55.2; Rossetto et al., 2014).
A in humans is 1 ng/kg (Gill, 1982).
TOXICODYNAMICS
SEROTYPES OF VETERINARY The toxicodynamics of botulinum toxins has been mostly
SIGNIFICANCE evaluated using commercialized versions of serotype A.
For this serotype, cleavage of less than 10% of SNAP-25
Serotypes A, B, C1, and D have been associated with out-
in the presynaptic nerve terminal results in 90%
breaks of botulism in domestic animals, livestock, poul-
muscular paralysis (Kalandakanond and Coffield, 2001).
try, and wildlife.
Spontaneous cholinergic neurotransmission in cultured
Veterinary Toxicology. DOI: http://dx.doi.org/10.1016/B978-0-12-811410-0.00055-6
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