Botulinum toxin: Mode of action and serotypes

Abstract

Botulinum toxin comprises a light and a heavy chain protein molecule. The heavy chain attaches the molecule to the nerve membrane, allowing the light chain to reach the site of action at the protein complex in the nerve ending. The toxin inhibits the release of acetylcholine at the neuromuscular junction and can inhibit contraction for 12 weeks before new nerve endings bud and restore function. The autonomic cholinergic receptors are also blocked, for up to 12 months. Central action can result from anterograde and retrograde axonal transport with secondary reduction of elements of the basal ganglia. Antinociceptive effects are due to blockades of pain and inflammatory mediator release. The different serotypes act on different elements of the vesicle-associated membrane protein/synaptosomal-associated protein-25/syntaxin protein complex. The development of antibodies to the protein complex is reported in 2% with serotype A (BOTOX) as opposed to 20% to 40% with serotype B (Myobloc).

Keywords

BOTOX, Dysport, neurotoxin, antinociceptive, serotype

A working knowledge of the pharmacology of botulinum toxin (BTX) is essential to understand the contraindications and complications of treatment with it.

Botulinum neurotoxins are metalloprotease polypeptides, comprising a protein molecule (150 Kd), which can be cleaved enzymatically into a heavy (H) (100 Kd) and a light (L) (50 Kd) chain ( Fig. 2.1 ). These chains are normally held together by a disulphide bond, which is heat labile. Disruption of this bond inactivates the neurotoxin. This explains why BTX must be stored at the correct temperature and reconstituted carefully, preserving the integrity of the two-chained molecule. Prior to reconstitution, characteristics of Incobotulinum toxin A (Xeomin) reflect the lack of a complexing protein with the neurotoxin, allowing lpng term stability and reduced immunogenicity.

BTX induces paralysis by blocking the release of acetylcholine at the skeletal alpha motor neurone neuromuscular junction, thereby inhibiting the transmission of nerve impulses across the synaptic junction to the motor end plate.

User Tip

Always consider possible central, as well as obvious peripheral, changes to the injected muscle following treatment (neuromodulation).

Muscular contraction: Normal cholinergic transmission ( fig. 2.2 )

Voluntary muscle contraction is a response to stimulation by action potentials passing along a nerve to the muscle. Once these action potentials reach a synapse at the neuromuscular junction, they stimulate an influx of calcium into the cytoplasm of the nerve ending. This increase in calcium concentration allows acetylcholine to fuse with the membrane, using a protein complex, before crossing the synapse and fusing with nicotinic receptors on the muscle fibre. The protein complex consists of three types of protein: vesicle-associated membrane protein (VAMP; synaptobrevin), synaptosomal-associated protein (SNAP)-25 and syntaxin.

Mode of action of botulinum toxin ( fig. 2.3 )

Acetylcholine depends on a protein complex for its release from the nerve ending into the synapse. BTX, using a specific enzyme in the L-chain, interacts with one component of the protein complex of the nerve terminal, thereby inhibiting the discharge of the acetylcholine. The protein attacked is specific to the different serotypes of BTX; for example BTX-A blocks SNAP-25, whereas BTX-B blocks VAMP. BTX-B acts on a different cytoplasmic protein complex. The secretion of acetylcholine is disrupted when the L-chain of the BTX-B molecule cleaves a protein called synaptobrevin, also known as VAMP. Clinical trials have shown BTX-B to be effective for the treatment of patients with cervical dystonia, including those resistant to BTX-A.