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BOTOX®™ :: Mode of Action
Illustration from the textbook Baumann L. "Cosmetic Dermatology: Principles
and Practice" McGraw Hill, Philadelphia, March 2002.
Botulinum toxin (BTX) induces chemical denervation of striated muscles by cleaving proteins required for the release of acetylcholine. The result is temporary flaccid paralysis of the injected muscles, which lasts approximately three to five months. As new neuromuscular junctions form, muscle function returns. There are seven serotypes (A-G) of BTX. Of these, type A was the first to be made available in the United States for medical uses (BOTOX®Ň). BTX-A is FDA approved for the treatment of blepharospasm, strabismus, and cervical dystonia.
Each of the seven serotypes of BTX are composed of three domains: the binding domain, the translocation domain, and the enzymatic domain. The binding domain, located on the heavy chain of the BTX molecule, is responsible for attaching to the acceptor on the presynaptic nerve terminal. Binding of botulinum toxin to its proper acceptor initiates endocytosis and internalization of the toxin heavy chain and light chain. Although the mechanisms of action of the translocation domain are not completely understood, it is responsible for getting the toxin into the endosome of the nerve terminal that contains ACh. Once inside the endosome, the acidic environment is believed to cause a change in the conformation of the toxin that allows the molecule to cross into the cytosol. i. The enzymatic domain of the light chain becomes functional in the cytosol and cleaves a protein in the SNARE complex that incapacitates this complex, preventing the fusion of acetylcholine vesicles, thus blocking extrusion of their contents. The SNARE complex is composed of synaptobrevin, SNAP-25 and syntaxin. BOTOX® cleaves a component of the SNARE complex known as SNAP -25.
i. Finkelstein A: Channels formed in phospholipid bilayer membranes by diphtheria, tetanus, botulinum and anthrax toxin. J Physiol 1990; 84:188
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