Title: Investigation of 'CRATKML' derived peptides as antidotes for the in vivo and in vitro paralytic effect of botulinum neurotoxin A

Authors: Joseph G. Potian, Baskaran Thyagarajan, Kormakur Hognason, Frank J. Lebeda, James J. Schmidt, Michael Adler, Joseph J. McArdle

Addresses: Department of Pharmacology and Physiology, UMDNJ – New Jersey Medical School, Newark, NJ 07103, USA. ' Department of Pharmacology and Physiology, UMDNJ – New Jersey Medical School, Newark, NJ 07103, USA. ' Department of Pharmacology and Physiology, UMDNJ – New Jersey Medical School, Newark, NJ 07103, USA. ' Integrated Toxicology Division, US Army Medical Research Institute of Infectious Diseases, Ft. Detrick, MD 21702-5012, USA; Combat Casualty Care Research Program, 504 Scott Street, Ft. Detrick, MD 21702-5012, USA. ' Department of Cell Biology and Biochemistry, Integrated Toxicology Division, US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA. ' Neurobehavioral Toxicology Branch, Analytical Toxicology Division, US Army Medical Research Institute of Chemical Defense, APG, MD 21010, USA. ' Department of Pharmacology and Physiology, UMDNJ – New Jersey Medical School, MSB-I626, 185 South Orange Avenue, Newark, NJ 07103, USA

Abstract: CRATKML-derived peptides (Cp) prevent Botulinum neurotoxin A (BoNT/A) cleavage of purified SNAP25. We tested the effects of four cell membrane permeable Cp analogs on BoNT/A poisoned neuromuscular junctions. In vitro pretreatment with these Cps did not prevent BoNT/A inhibition of neuromuscular transmission (NMT). In vivo pretreatment with these Cps did not protect NMT against BoNT/A. The lack of prophylactic effect paralleled a lack of therapeutic effect on BoNT/A intoxicated mice. These data demonstrate that although Cps are effective BoNT/A antagonists in cell free systems, they are not effective against in vitro or in vivo BoNT/A actions of motor nerve endings.

Keywords: SNAP25; MEI; metalloendoprotease inhibitors; neurotransmitter release; botulinum neurotoxin; BoNT/A; BoNT; botulism; mouse; diaphragm; EDL; extensor digitorum longus; twitch tension; secretory vesicles; neuromuscular transmission; motor nerve endings; CRATKML-derived peptides.

DOI: 10.1504/TBJ.2010.039115

The Botulinum Journal, 2010 Vol.1 No.4, pp.407 - 417

Published online: 17 Mar 2011 *

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