Effects of hydroxamate metalloendoprotease inhibitors on botulinum neurotoxin A poisoned mouse neuromuscular junctions

NEUROPHARMACOLOGY

卷:58

Article

Thyagarajan, Baskaran¹  Potian, Joseph G.¹  Garcia, Carmen C.¹  Hognason, Kormakur¹  Capkova, Katerina^2,3  Moe, Scott T.⁴  Jacobson, Alan R.⁴  Janda, Kim D.^2,3  McArdle, Joseph J.¹ 

[1] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Physiol & Pharmacol, Newark, NJ 07103 USA

[2] Scripps Res Inst, Dept Chem, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA

[3] Scripps Res Inst, Worm Inst Res & Med WIRM, La Jolla, CA 92037 USA

[4] Absolute Sci Inc, Lexington, MA 02421 USA

关键词: Botulinum neurotoxin A;    Metalloendoprotease inhibitors;    Neurotransmitter release;    Neuroparalysis;    Neuromuscular junction;    Hydroxamates;   

DOI  :  10.1016/j.neuropharm.2010.02.014

来源: Elsevier

【 摘 要 】

Currently the only therapy for botulinum neurotoxin A (BoNT/A) poisoning is antitoxin. Antidotes that are effective after BoNT/A has entered the motor nerve terminals would dramatically benefit BoNT/A therapy. Inhibition of proteolytic activity of BoNT/A light chain by metalloendoprotease inhibitors (MEIs) is under development. We tested the effects of MEIs on in vitro as well as in vivo BoNT/A poisoned mouse nerve-muscle preparations (NMPs). The K-i for inhibition of BoNT/A metalloendoprotease was 0.40 and 0.36 mu M, respectively, for 2,4-dichlorocinnamic acid hydroxamate (DCH) and its methyl derivative, ABS 130. Acute treatment of nerve-muscle preparations with 10 pM BoNT/A inhibited nerve-evoked muscle twitches, reduced mean quantal content, and induced failures of endplate currents (EPCs). Bath application of 10 mu M DCH or 5 mu M ABS 130 reduced failures, increased the quantal content of EPCs, and partially restored muscle twitches after a delay of 40-90 min. The restorative effects of DCH and ABS 130, as well as 3,4 diaminopyridine (DAP) on twitch tension were greater at 22 degrees C compared to 37 degrees C. Unlike DAP, neither DCH nor ABS 130 increased Ca2+ levels in cholinergic Neuro 2a cells. Injection of MEIs into mouse hind limbs before or after BoNT/A injection neither prevented the toe spread reflex inhibition nor improved muscle functions. We suggest that hydroxamate MEIs partially restore neurotransmission of acutely BoNT/A poisoned nerve-muscle preparations in vitro in a temperature dependent manner without increasing the Ca2+ levels within motor nerve endings. (C) 2010 Elsevier Ltd. All rights reserved.

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