The botulinum neurotoxin is such a potent and deadly toxin that the U.S. Centers for Disease Control (CDC) lists it as a category A bioterrorism agent. Some of its additional characteristic properties are that is highly selective and has a long duration of activity. This has made it possible for this agent to be used therapeutically, at controlled doses, for focal dystonias, wound healing and used cosmetically to decrease the evidence of wrinkling of the skin associated with aging.
Botulinum neurotoxin is produced by the Clostridium botulinum bacteria – a Gram-positive, spore-forming microorganism that requires an environment lacking in oxygen to grow. Individuals can be exposed to this deadly toxin either through ingestion or inhalation. Certain vegetables when improperly canned are notorious for providing the right environment for the growth of the botulinum bacteria and, therefore, the production of botulinum neurotoxin.
Once an individual has been exposed to this deadly toxin, it finds its way into the bloodstream and attacks the nervous system, resulting in muscle paralysis and autonomic dysfunction. It is the latter capability that can prove fatal; since, the autonomic nervous system controls such basic functions as breathing and maintaining the rhythm of the heart. It has long been known that botulinum neurotoxin's mode of action is through the proteolysis – breakdown of proteins – of a key protein involved in the release of acetylcholine from nerve terminals. Acetylcholine is an essential neurotransmitter in a significant category of cells in the human nervous system.
Structurally, botulinum neurotoxin is a protein. This poses an interesting question: given its protein structure how is it able to survive the onslaught of the digestive system when it is ingested? There must be some mechanism that explains how it can survive the acidity of the stomach and the digestive proteolytic enzymes of the stomach and small intestine.
The answer to this question has recently been resolved through the efforts of Dr. Shenyan Gu and his colleagues at the Center for Neuroscience, Aging and Stem Cell Research at the Sanford-Burnham Medical Research Institute in La Jolla California. They discovered through exhaustive studies of the structure of the intact bioactive toxin that it exists as a complex with four additional proteins associated with botulinum neurotoxin. One of these associated proteins, referred to as nontoxic non-hemagglutinin (NTNHA), is responsible for protecting the primary toxin from the acidity found in the stomach and for its protection from the proteolytic activity of trypsin produced by the stomach.
This finding not only helps elucidate the complete mechanism of action of botulinum neurotoxin but also suggests that inhibitors could be designed to weaken the necessary interaction between the toxin and its associated proteins early in the intoxication phase of the infection.