The Role of Systemic Handling in the Pathophysiologic Actions of Botulinum Toxin

Al-Saleem, Fetweh H.; Ancharski, Denise M.; Ravichandran, Easwaran; Joshi, Suresh G.; Singh, Ajay K.; Gong, Yujing; Simpson, Lance L.

doi:10.1124/jpet.108.136242

Cited by 29 publications

(31 citation statements)

References 26 publications

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“…model for evaluating antitoxins; the window of opportunity for treatment is too small. The remaining toxin in the serum was cleared slowly, with an elimination t 1/2 of about 4 h, consistent with findings by other groups using different methods (2). This persistent pool of toxin is the main target of current antitoxin therapies.…”

Section: Discussionsupporting

confidence: 73%

“…The t 1/2␤ likely represents clearance of the toxin from the blood. Both t 1/2␣ and t 1/2␤ were comparable to the 61-min t 1/2␣ and 600-min t 1/2␤ of BoNT/B and the overall BoNT/A t 1/2 of 231 min previously determined in mice with radiolabeled toxins (2,21).…”

Section: Resultsmentioning

confidence: 60%

“…With this assay, the serum t 1/2 of ciBoNT/A was determined (Fig. 4) and found to be comparable to those measured for BoNT/B by radiolabeling and toxin inactivation (2). The serum pharmacokinetic data for ciBoNT/A showed a remarkably strong correlation with the MAb rescue profiles after i.v.…”

Section: Discussionmentioning

confidence: 66%

“…By using 125 I-labeled BoNT/A and BoNT/B, the biological halflives (t 1/2 s) of such toxins have been determined in blood (2,21). Furthermore, BoNTs were shown not to go through biotransformation during epithelial membrane translocation or by interaction with blood components.…”

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confidence: 99%

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Antibody Protection against Botulinum Neurotoxin Intoxication in Mice

et al. 2009

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Adulteration of food or feed with any of the seven serotypes of botulinum neurotoxin (BoNT) is a potential bioterrorism concern. Currently, there is strong interest in the development of detection reagents, vaccines, therapeutics, and other countermeasures. A sensitive immunoassay for detecting BoNT serotype A (BoNT/A), based on monoclonal antibodies (MAbs) F1-2 and F1-40, has been developed and used in complex matrices. The epitope for F1-2 has been mapped to the heavy chain of BoNT/A, and the epitope of F1-40 has been mapped to the light chain. The ability of these MAbs to provide therapeutic protection against BoNT/A intoxication in mouse intravenous and oral intoxication models was tested. High dosages of individual MAbs protected mice well both pre-and postexposure to BoNT/A holotoxin. A combination therapy consisting of antibodies against both the light and heavy chains of the toxin, however, significantly increased protection, even at a lower MAb dosage. An in vitro peptide assay for measuring toxin activity showed that pretreatment of toxin with these MAbs did not block catalytic activity but instead blocked toxin entry into primary and cultured neuronal cells. The timing of antibody rescue in the mouse intoxication models revealed windows of opportunity for antibody therapeutic treatment that correlated well with the biologic half-life of the toxin in the serum. Knowledge of BoNT intoxication and antibody clearance in these mouse models and understanding of the pharmacokinetics of BoNT are invaluable for future development of antibodies and therapeutics against intoxication by BoNT.Botulinum neurotoxins (BoNTs) are considered some of the most potent toxins known and are potential bioterrorist threat agents. Yet, BoNT serotype A (BoNT/A) and BoNT/B are also used therapeutically in a wide array of medical conditions, such as dystonia and eye disorders like strabismus and blepharospasms, for pain management, and more (3, 25). Thus, there is a need to protect humans and animals against toxin exposure from contaminated food or feed and yet preserve the medical benefits of BoNT. A better understanding of the biology of the toxin, such as toxin distribution and mechanisms of toxin neutralization following intoxication, is needed to aid further development of improved therapies, as well as bona fide use of toxin to treat serious medical conditions.BoNTs are 150-kDa endopeptidase toxins that are produced by Clostridium botulinum, C. butyricum, and C. baratii (20,26,27). The toxin polypeptide is cleaved upon secretion from the cell by bacterial proteases or proteases in the animal host into a disulfide bond-linked dipeptide consisting of a 100-kDa heavy chain (Hc) and a 50-kDa light chain (Lc). The 50-kDa Lc contains the active site or catalytic domain that targets the soluble N-ethylmaleimide-sensitive factor attachment protein receptor. Specifically, the synaptosome-associated 25-kDa protein (SNAP25) is the target for BoNT/A. Cleavage of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor ...

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Section: Discussionsupporting

confidence: 73%

Section: Resultsmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 99%

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Antibody Protection against Botulinum Neurotoxin Intoxication in Mice

et al. 2009

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“…The antibody was administered well in advance of toxin challenge (18 h), which afforded ample time for distribution to the general circulation on the basal side of epithelial cells (2). When mice were passively immunized with anti-HA35 antibodies and then challenged i.n.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Mechanisms That Underlie Absorption of Botulinum Toxin by the Inhalation Route

et al. 2012

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e Botulinum toxin is a highly potent oral and inhalation poison, which means that the toxin must have an efficient mechanism for penetration of epithelial barriers. To date, three models for toxin passage across epithelial barriers have been proposed: (i) the toxin itself undergoes binding and transcytosis; (ii) an auxiliary protein, HA35, transports toxin from the apical to the basal side of epithelial cells; and (iii) an auxiliary protein, HA35, acts on the basal side of epithelial cells to disrupt tight junctions, and this permits paracellular flux of toxin. These models were evaluated by studying toxin absorption following inhalation exposure in mice. Three types of experiments were conducted. In the first, the potency of pure neurotoxin was compared with that of progenitor toxin complex, which contains HA35. The results showed that the rate and extent of toxin absorption, as well as the potency of absorbed toxin, did not depend upon, nor were they enhanced by, the presence of HA35. In the second type of experiment, the potencies of pure neurotoxin and progenitor toxin complex were compared in the absence or presence of antibodies on the apical side of epithelial cells. Antibodies directed against the neurotoxin protected against challenge, but antibodies against HA35 did not. In the final type of experiment, the potency of pure neurotoxin and toxin complex was compared in animals pretreated to deliver antibodies to the basal side of epithelial cells. Once again, antibodies directed against the neurotoxin provided resistance to challenge, but antibodies directed against HA35 did not. Taken collectively, the data indicate that the toxin by itself is capable of crossing epithelial barriers. The data do not support any hypothesis in which HA35 is essential for toxin penetration of epithelial barriers.

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Absorption and Transport of Botulinum Neurotoxins

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Connan

2014

Molecular Aspects of Botulinum Neurotoxin

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Botulinum neurotoxin (BoNT) is a potent toxin, which blocks the neurotransmitter release at neuromuscular junctions. BoNT can be acquired from the digestive tract (food-borne botulism, Clostridium botulinum intestinal colonization), respiratory tract (inhalational botulism), or wound (wound botulism). BoNT associates to nontoxic proteins (ANTPs), which have a main role in toxin protection against acidic pH and proteases, especially in the gastrointestinal tract. BoNT, which enters through the digestive or respiratory tract, has to first cross the epithelial barrier. This is achieved by a receptor-mediated transcytosis, which delivers the whole and active toxin at the basolateral side of epithelial cells. ANTPs containing hemagglutinins (HAs) may have an additional role in altering the intercellular junctions and facilitating toxin passage through the paracellular way. Then, BoNT disseminates locally and at distance via the blood/lymph circulation and possibly via a retrograde axonal transport to the target motor neuron endings, where the toxin uses an endocytic pathway permitting the release of the light (L)-chain into the cytosol and its subsequent proteolytic activity towards the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins involved in the neurotransmitter exocytosis.

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The Role of Systemic Handling in the Pathophysiologic Actions of Botulinum Toxin

Cited by 29 publications

References 26 publications

Antibody Protection against Botulinum Neurotoxin Intoxication in Mice

Antibody Protection against Botulinum Neurotoxin Intoxication in Mice

Analysis of the Mechanisms That Underlie Absorption of Botulinum Toxin by the Inhalation Route

Absorption and Transport of Botulinum Neurotoxins

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