Botulinum toxin A — 360°
Date:
01.04.2015
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Botulism is a severe, sometimes fatal, foodborne-illness caused by Clostridium botulinum, a common soil-dwelling bacterium. Improperly stored or prepared foodstuffs that come into contact with soil can become contaminated with C. botulinum spores that germinate under anoxic conditions. This results in the production of the botulinum toxin, one of the most powerful toxins known. About 1 gram of pure toxin was used commercially all over the world in 2011 (1), and two kilos is roughly enough to provide a lethal dose to the entire population of the Earth.

Botulinum toxin is a paralytic neurotoxin that acts on the neuromuscular motor neurons and prevents them from releasing acetylcholine required for muscle contraction. There are 7 different types of botulinum toxin, type A-G, that are distinguished by their structure and mechanism of action. (2) All types except F and G cause poisoning in humans.

Botulinum toxin is initially synthesized as a protoxin protein that is cleaved by an extracellular protease. The resulting heavy (100 kDa) and light (50 kDa) chains remain linked via a disulfide bond in the mature toxin. The light chain itself is a zinc protease that will cleave vesicle fusion proteins like SNAP-25 in presynaptic motor neurons, blocking the release of acetylcholine. This causes flaccid muscle paralysis and can be deadly if the toxin attacks neurons innervating respiratory muscles.

As the toxin matures, botulinum toxin forms an acid-stable complex with accessory proteins like hemagglutinin and NTNH that protect it from being destroyed in the digestive tract. The toxin can then enter the bloodstream through the epithelium of the small intestine. However, botulinum toxin can also enter the blood when inhaled as an aerosol, which has lead to the development of botulinum toxin as a biological weapon. To protect soldiers from possible poisoning during World War II, the U.S. Defense Department developed the first pentavalent vaccine against botulinum toxins A-E. Vaccines are effective against toxin in the blood, but after being absorbed by neurons the toxin becomes unavailable for immune recognition. Thus, antitoxins are only effective immediately following exposure. Once in the neurons, the toxin can persist for weeks to months.

Botulinum toxin, however, has medical uses as well. Due to its ability to block neuromuscular transmission, it is used at very low concentrations to relieve muscle spasms in cervical dystonia, cerebral palsy, and blepharospasm— the involuntary contraction of eyelid muscles. More recently, preparations of type A botulinum toxin known as “Botox” or “Dysport” (pictured) have been used for the cosmetic treatment of wrinkles as it causes a temporary relaxation of facial muscles.

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A.V. Trapeznikov
Corporate director, Board member of RUSNANO