Thioredoxin and its reductase are present on synaptic vesicles, and their inhibition prevents the paralysis induced by botulinum neurotoxins

Cell Rep. 2014 Sep 25;8(6):1870-1878. doi: 10.1016/j.celrep.2014.08.017. Epub 2014 Sep 15.

Abstract

Botulinum neurotoxins consist of a metalloprotease linked via a conserved interchain disulfide bond to a heavy chain responsible for neurospecific binding and translocation of the enzymatic domain in the nerve terminal cytosol. The metalloprotease activity is enabled upon disulfide reduction and causes neuroparalysis by cleaving the SNARE proteins. Here, we show that the thioredoxin reductase-thioredoxin protein disulfide-reducing system is present on synaptic vesicles and that it is functional and responsible for the reduction of the interchain disulfide of botulinum neurotoxin serotypes A, C, and E. Specific inhibitors of thioredoxin reductase or thioredoxin prevent intoxication of cultured neurons in a dose-dependent manner and are also very effective inhibitors of the paralysis of the neuromuscular junction. We found that this group of inhibitors of botulinum neurotoxins is very effective in vivo. Most of them are nontoxic and are good candidates as preventive and therapeutic drugs for human botulism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Botulinum Toxins / toxicity*
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Curcumin / pharmacology
  • Curcumin / therapeutic use
  • Cytoplasm / metabolism
  • Disulfides / pharmacology
  • Disulfides / therapeutic use
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use
  • Male
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism
  • Paralysis / etiology
  • Paralysis / prevention & control*
  • Serotyping
  • Synaptic Vesicles / drug effects*
  • Synaptic Vesicles / enzymology*
  • Synaptosomal-Associated Protein 25 / metabolism
  • Thioredoxin-Disulfide Reductase / antagonists & inhibitors
  • Thioredoxin-Disulfide Reductase / metabolism*
  • Thioredoxins / antagonists & inhibitors
  • Thioredoxins / metabolism*

Substances

  • Disulfides
  • Enzyme Inhibitors
  • Imidazoles
  • Synaptosomal-Associated Protein 25
  • Thioredoxins
  • IV 2 compound
  • Thioredoxin-Disulfide Reductase
  • Botulinum Toxins
  • Curcumin