Page 786 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Botulinum Neurotoxins Chapter | 55 745

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FIGURE 55.2 Botulinum toxin disruption of synaptic vesicle release. Adapted from Rossetto, O., Pirazzini, M., Montecucco, C. Botulinum neurotox-
ins: genetic, structural, and mechanistic insights. Nat. Rev. Microbiol. 2014 Aug;12(8):535 549. (Cortesy of Rossetto O).

biologically active toxin within the general circulation gated ion channel function, receptor translocation to the
acts as a “holding compartment” which contributes to the plasma membrane, neurite extension and dendrite and
severity and extent of the disease; (4) the high affinity of axonal growth (which may further impair recovery from
botulinum toxin/A heavy chain to dual ganglioside- classical botulism).
protein acceptors at the peripheral nerve terminals; (5) the Apart from its effects on motor neurons, botulinum
capacity of a single light chain metalloprotease to inacti- toxins have antinociceptive effects and have been devel-
vate large numbers of its toxicological target proteins; (6) oped as potential therapies for subacute to chronic pain.
in the cytosol, the light chains are very stable and resis- These effects are, at least in part, dependent on axonal
tant to proteasomal degradation, resulting in long duration transport of the toxin into the CNS (Matak and Lackovi´ c,
effects; (7) cleavage of only a small proportion of the tox- 2014). Botulinum toxins also undergo axonal transport in
icological target proteins results in a very large overall motor neurons; however the clinical significance of this is
biological effect; and (8) in practical terms, recovery uncertain.
requires nerve sprouting and the synthesis of new neuro-
muscular junctions.
Botulinum toxins also affect in vitro neurotransmis- QUANTIFICATION OF NEUROMUSCULAR
sion associated with serotonin, dopamine, noradrenalin,
BLOCKING POTENCY
glutamate, GABA, encephalin, glycine, substance P,
ATP, and calcitonin gene related peptide. Botulinum The classical, and still standard, assay of potency is the
toxins tend to have greater efficacy on excitatory neuro- mouse bioassay. One mouse unit (MU) is the amount of
transmitters (acetylcholine, glutamate), and inhibitory botulinum toxin A required to kill 50% of a group of
transmitters (e.g., GABA), which may explain the clini- 20 g Swiss Webster mice within 3 days of IP injection.
cal sign of “dullness” seen in some animals (notably Approximately 1 ng of botulinum A is equivalent to
horses; Verderio et al., 2007). Notably, the effects of 20 MU. A more pharmacologically relevant unit,
botulinum toxins are not necessarily confined to neuro- the median paralysis unit (MPU) was developed in 1995
nal synapses, e.g., botulinum toxin A inhibits the to better characterize the biological activities of the
ectopic vesicular release of glutamate and ATP in olfac- pharmaceutical versions of botulinum toxins (Pearce
tory receptor axons (Thyssen et al., 2010) and blocks et al., 1995). The unit is based on a regional chemode-
several nonneuronal SNAP-25 dependent effects, nota- nervation following IM injection rather than mortality.
bly insulin release from pancreatic beta cells, acetylcho- One MPU is the ED 50 producing complete hind limb
line release from chromaffin cells, acetylcholine release paralysis following IM injection into the mouse hind
from sciatic Schwann cells, glutamate release from limb and is equivalent to an amount of toxin in the pico-
21
astrocytes, Ca channel and possibly other voltage gram range.