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01.05.2015 | Original Article

Src Family Kinase Inhibitors Antagonize the Toxicity of Multiple Serotypes of Botulinum Neurotoxin in Human Embryonic Stem Cell-Derived Motor Neurons

verfasst von: Erkan Kiris, James C. Burnett, Jonathan E. Nuss, Laura M. Wanner, Brian D. Peyser, Hao T. Du, Glenn Y. Gomba, Krishna P. Kota, Rekha G. Panchal, Rick Gussio, Christopher D. Kane, Lino Tessarollo, Sina Bavari

Erschienen in: Neurotoxicity Research | Ausgabe 4/2015

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Abstract

Botulinum neurotoxins (BoNTs), the causative agents of botulism, are potent inhibitors of neurotransmitter release from motor neurons. There are currently no drugs to treat BoNT intoxication after the onset of the disease symptoms. In this study, we explored how modulation of key host pathways affects the process of BoNT intoxication in human motor neurons, focusing on Src family kinase (SFK) signaling. Motor neurons derived from human embryonic stem (hES) cells were treated with a panel of SFK inhibitors and intoxicated with BoNT serotypes A, B, or E (which are responsible for >95 % of human botulism cases). Subsequently, it was found that bosutinib, dasatinib, KX2-391, PP1, PP2, Src inhibitor-1, and SU6656 significantly antagonized all three of the serotypes. Furthermore, the data indicated that the treatment of hES-derived motor neurons with multiple SFK inhibitors increased the antagonistic effect synergistically. Mechanistically, the small molecules appear to inhibit BoNTs by targeting host pathways necessary for intoxication and not by directly inhibiting the toxins’ proteolytic activity. Importantly, the identified inhibitors are all well-studied with some in clinical trials while others are FDA-approved drugs. Overall, this study emphasizes the importance of targeting host neuronal pathways, rather than the toxin’s enzymatic components, to antagonize multiple BoNT serotypes in motor neurons.

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Titel: Src Family Kinase Inhibitors Antagonize the Toxicity of Multiple Serotypes of Botulinum Neurotoxin in Human Embryonic Stem Cell-Derived Motor Neurons
verfasst von: Erkan Kiris
James C. Burnett
Jonathan E. Nuss
Laura M. Wanner
Brian D. Peyser
Hao T. Du
Glenn Y. Gomba
Krishna P. Kota
Rekha G. Panchal
Rick Gussio
Christopher D. Kane
Lino Tessarollo
Sina Bavari
Publikationsdatum: 01.05.2015
Verlag: Springer US
Erschienen in: Neurotoxicity Research / Ausgabe 4/2015
Print ISSN: 1029-8428
Elektronische ISSN: 1476-3524
DOI: https://doi.org/10.1007/s12640-015-9526-z

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