Page 785 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

744 SECTION | XI Bacterial and Cyanobacterial Toxins

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FIGURE 55.1 Botulinum toxin structure.

autonomic neurons is reduced to less than 20% (i.e., near
TABLE 55.1 Neuronal Cellular Targets of complete synaptic paralysis) when less than 20% of pre-
Botulinum Toxins synaptic nerve terminal SNAP-25 is cleaved (Lawrence
et al., 2013).
Botulinum Molecular Key Effect
The effects of serotype A light chains on SNAP-25
Toxin Target of the
lasts for about 4 days (i.e., equivalent to SNAP-25 turn-
Serotypes Light Chain
over time in the synaptic terminal; Bartels et al., 1994).
a
A Cleaves SNAP- SNAP-25 is presynaptic However, this does not correlate with the persistence of
25 membrane protein
E serotype A-induced paralysis which may last several
required for fusion of
neurotransmitter- months. The unusual cytosolular stability of the proteo-
containing vesicles lytic form of the light chain (at least 180 days in vivo and
80 days in vitro in rodent tissues) and its resistance to
B Cleaves VAMP VAMP (syn:
synaptobrevin) is a small proteasomal degradation are the major reasons for the
D
integral membrane long duration of botulinum toxin A-induced paralysis
F protein found in (Antonucci et al., 2008; Keller et al., 1999). Consistent
neurotransmitter
G with this conclusion is the finding that the light chains of
secretory vesicles. botulinum toxin serotype E are more susceptible to pro-
Cleavage of VAMP
blocks neurotransmitter teasomal degradation, resulting in its shorter duration of
exocytosis and action cf serotype A.
endocytosis Overall, the major pharmacokinetic and pharmacody-
C1 Syntaxin The syntaxin domain namic factors that combine to cause the exquisitely high
contains a soluble NSF b toxicity of botulinum toxins are: (1) although it is a large
attachment protein protein, a large fraction of ingested toxin is systemically
(SNARE) that acts as the absorbed; (2) the long elimination half-life of botulinum
docking site for SNAP-25
toxin/A in the systemic circulation acts as a allows distri-
a
SNAP-25 5 Synaptosomal-associated protein 25. bution to peripheral tissues and entry into peripheral nerve
b
NSF 5 N-ethylmaleimide sensitive fusion proteins.
terminals; (3) the relatively long persistence of