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Antidotes to Botulinum Neurotoxin

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Biological Toxins and Bioterrorism

Part of the book series: Toxinology ((TOXI))

Abstract

Botulinum neurotoxins (BoNTs) are the most potent neurotoxins and are potential biothreat agents. All seven serotypes of BoNTs (/A through/G) consist of a 100 kDa heavy chain (Hc) and a 50 kDa light chain (Lc) linked by a single disulfide bond. BoNT Hc binds to its receptors on the neural membrane and sets the stage for endocytosis at the motor nerve terminals (MNTs). Within early endosomes BoNT undergoes pH-dependent separation of the Hc and Lc. The Hc translocates the Lc into the cytosol where BoNTs proteolyze selective SNARE complex proteins resulting in the attenuation of acetylcholine (ACh) release at MNT. This results in a flaccid, long-lasting neuroparalysis of the skeletal muscles. The persistence of BoNT/A, the principal serotype, Lc protease at the MNT accounts for the long-lasting paralysis and the difficulty to develop therapeutics against BoNT/A. The ease of production and dissemination of the neurotoxin makes it as a viable biothreat agent. The quest for antidotes to treat botulism is an ongoing process. Efforts to develop antidotes against BoNTs have also advanced our knowledge about endoexocytic mechanisms that mediate BoNT signaling at the MNT. This review describes the antidotes that have prophylactic and therapeutic potential to counteract BoNTs in cellular and neuromuscular model systems by neutralizing the toxin in the blood, preventing the binding/internalization of the toxin, inhibiting the translocation of the Lc from early endosomes to cytosol, disrupting the catalytic activity of the Lc endoprotease, and/or restoring neurotransmission by increasing presynaptic Ca2+-triggered exocytosis.

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Authors and Affiliations

  1. College of Health Sciences, School of Pharmacy, University of Wyoming, Laramie, WY, USA

    Baskaran Thyagarajan

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  1. Baskaran Thyagarajan
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Correspondence to Baskaran Thyagarajan .

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Editors and Affiliations

  1. Venom and Toxin Research Programme, Department of Anatomy, Yong Loo Lin School of Medicine National University of Singapore, Singapore, Singapore

    P. Gopalakrishnakone

  2. Medical Toxicology Research Centre Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Mahdi Balali-Mood

  3. Data and Technology Innovation, Australian Institute of Marine Science, Townsville, QLD, Australia

    Lyndon Llewellyn

  4. Botulinum Research Center, Institute of Advanced Sciences, Dartmouth, MA, USA

    Bal Ram Singh

  5. Prime Bio, Inc., Dartmouth, MA, USA

    Bal Ram Singh

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Thyagarajan, B. (2015). Antidotes to Botulinum Neurotoxin. In: Gopalakrishnakone, P., Balali-Mood, M., Llewellyn, L., Singh, B.R. (eds) Biological Toxins and Bioterrorism. Toxinology. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5869-8_4

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