Abstract
Botulinum neurotoxins (BoNTs) are the most poisonous substances known and cause the severe disease botulism. BoNTs have also been remarkably effective as therapeutics in treating many neuronal and neuromuscular disorders. One of the hallmarks of BoNTs, particularly serotype A, is its long persistence of 2-6 months in patients at concentrations as low as fM or pM. The mechanisms for this persistence are currently unclear. In this study we determined the persistence of the BoNT/A subtypes 1 through 5 in primary rat spinal neurons. Remarkably, the duration of intracellular enzymatic activity of BoNT/A1, /A2, /A4 and /A5 was shown to be at least 10 months. Conversely, the effects of BoNT/A3 were observed for up to ∼5 months. An intermittent dosing with BoNT/E showed intracellular activity of the shorter acting BoNT/E for 2–3 weeks, followed by reoccurrence and persistence of BoNT/A-induced SNAP-25 cleavage products.
Highlights
Botulinum neurotoxins (BoNTs), produced by neurotoxigenic clostridia, have been recognized as the cause of botulism for over a century [1]
To determine whether BoNT/A3, /A4, and /A5 subtypes have long durations of action as seen previously with BoNT/ A1 and BoNT/A2 [9], primary rat spinal cord (RSC) cells were exposed to the minimal amount of toxin required to generate,100% BoNT/A-induced SNAP-25 cleavage (SNAP-25A) within 48 h
The results presented here show that BoNT/A3 has significantly shorter duration of action in RSC cultured neurons than
Summary
Botulinum neurotoxins (BoNTs), produced by neurotoxigenic clostridia, have been recognized as the cause of botulism for over a century [1]. BoNTs have been categorized into seven immunologically distinct serotypes, A through G [4]. Introduction of an 8th serotype (H) has been suggested [5,6]; further research is needed to validate this classification. Many subtypes that differ in their amino acid sequences have been demonstrated for most serotypes [7]. After local injection in humans, the paralytic effects of BoNT/A1 has the longest duration of action and diminish only after 2–6 months post injection [8], but the mechanism of recovery is not well understood
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