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Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis
Shunmoogum A. Patten, … , J. Alexander Parker, Pierre Drapeau
Shunmoogum A. Patten, … , J. Alexander Parker, Pierre Drapeau
Published November 16, 2017
Citation Information: JCI Insight. 2017;2(22):e97152. https://doi.org/10.1172/jci.insight.97152.
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Research Article Clinical trials Neuroscience

Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis

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Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal disorder with no effective treatment. We used simple genetic models of ALS to screen phenotypically for potential therapeutic compounds. We screened libraries of compounds in C. elegans, validated hits in zebrafish, and tested the most potent molecule in mice and in a small clinical trial. We identified a class of neuroleptics that restored motility in C. elegans and in zebrafish, and the most potent was pimozide, which blocked T-type Ca2+ channels in these simple models and stabilized neuromuscular transmission in zebrafish and enhanced it in mice. Finally, a short randomized controlled trial of sporadic ALS subjects demonstrated stabilization of motility and evidence of target engagement at the neuromuscular junction. Simple genetic models are, thus, useful in identifying promising compounds for the treatment of ALS, such as neuroleptics, which may stabilize neuromuscular transmission and prolong survival in this disease.

Authors

Shunmoogum A. Patten, Dina Aggad, Jose Martinez, Elsa Tremblay, Janet Petrillo, Gary A.B. Armstrong, Alexandre La Fontaine, Claudia Maios, Meijiang Liao, Sorana Ciura, Xiao-Yan Wen, Victor Rafuse, Justin Ichida, Lorne Zinman, Jean-Pierre Julien, Edor Kabashi, Richard Robitaille, Lawrence Korngut, J. Alexander Parker, Pierre Drapeau

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Figure 1

Chemical genetic screen identified 13 compounds as neuroprotective in models of ALS.

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Chemical genetic screen identified 13 compounds as neuroprotective in mo...
Chemical libraries (3,850 compounds) were first screened in a C. elegans TDP-43 model, and positive hits were tested on zebrafish models of ALS. Individual or small numbers of animals were transferred into multiwell dishes in which different test compounds were present and incubated for 6 hours (C. elegans) or overnight (zebrafish). We identified 13 compounds that improved motor behavior (motility) phenotypes in mutant TDP-43 (mTDP43) C. elegans. These positive hits were then tested on mTDP-43 zebrafish at various concentrations (1–20 μM). We identified 10 active compounds (highlighted in bold) in our zebrafish model, and the most potent compound was found to be pimozide, which was active at 1 μM.

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