Botulinum Neurotoxins as Two-Faced Janus Proteins

Botulinum neurotoxins are synthetized by anaerobic, spore-forming bacteria that inhibit acetylcholine release at the level of the neuromuscular and autonomic cholinergic junctions, thus inducing a series of symptoms, the most relevant of which is flaccid paralysis. At least seven serotypes and over 40 subtypes are known, and they are among the most poisonous natural substances. There are different forms of botulism according to the route of contamination, but the clinical manifestation of descending symmetric flaccid paralysis is consistent, regardless of the route of contamination. It is very severe and potentially lethal. The induced paralysis lasts as long as the toxin is active, with variable length, according to the serotype of the toxin. This transient activity, as well as the precise mechanism of action, are the basis for the rationale behind use of the toxin in therapy for several clinical conditions, particularly, spastic conditions, as well as chronic migraine and axillary hyperhidrosis. The toxin has also been approved for the reduction in facial wrinkles; all these clinical applications, coupled with the toxin's risks, have earned botulinum the title of a two-faced Janus protein. No approved vaccines are currently available, andthe only approved antidotes are the human specific intravenous immunoglobulins for infant botulism and the heptavalent equine immunoglobulins/(F(ab')² for adults. Nanobodies, which show great promise, may penetrate neuronal cells to inactivate the toxin within the cytoplasm, and Ebselen, a non-toxic, economic, small-molecule inhibitor, has the characteristic of inhibiting the toxin irrespective of the serotype.