Inhibition of botulinum neurotoxins interchain disulfide bond reduction prevents the peripheral neuroparalysis of botulism

Giulia Zanetti, Domenico Azarnia Tehran, Marcon Pirazzini, Thomas Binz, Clifford Shone, Silvia Fillo, Florigio Lista, Ornella Rossetto, Cesare Montecucco*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    26 Citations (Scopus)

    Abstract

    Botulinum neurotoxins (BoNTs) form a growing family of metalloproteases with a unique specificity either for VAMP, SNAP25 or syntaxin. The BoNTs are grouped in seven different serotypes indicated by letters from A to G. These neurotoxins enter the cytosol of nerve terminals via a 100 kDa chain which binds to the presynaptic membrane and assists the translocation of a 50 kDa metalloprotease chain. These two chains are linked by a single disulfide bridge which plays an essential role during the entry of the metalloprotease chain in the cytosol, but thereafter it has to be reduced to free the proteolytic activity. Its reduction is mediated by thioredoxin which is continuously regenerated by its reductase. Here we show that inhibitors of thioredoxin reductase or of thioredoxin prevent the specific proteolysis of VAMP by the four VAMP-specific BoNTs: type B, D, F and G. These compounds are effective not only in primary cultures of neurons, but also in preventing the in vivo mouse limb neuroparalysis. In addition, one of these inhibitors, Ebselen, largely protects mice from the death caused by a systemic injection. Together with recent results obtained with BoNTs specific for SNAP25 and syntaxin, the present data demonstrate the essential role of the thioredoxin-thioredoxin reductase system in reducing the interchain disulfide during the nerve intoxication mechanism of all serotypes. Therefore its inhibitors should be considered for a possible use to prevent botulism and for treating infant botulism.

    Original languageEnglish
    Pages (from-to)522-530
    Number of pages9
    JournalBiochemical Pharmacology
    Volume98
    Issue number3
    DOIs
    Publication statusPublished - 1 Dec 2015

    Bibliographical note

    Publisher Copyright:
    © 2015 Elsevier Inc. All rights reserved.

    Keywords

    • Botulinum neurotoxins
    • Botulism
    • Ebselen
    • Inhibitors
    • Peripheral neuroparalysis
    • Thioredoxin system

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