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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. doi:10.1172/jci.insight.97152.
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Categories: 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 5

Pimozide restores synaptic transmission in C. elegans and zebrafish mutant TDP-43.

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Pimozide restores synaptic transmission in C. elegans and zebrafish muta...
(A and B) Cholinergic neuronal transmission was measured by determining the onset of paralysis induced by the cholinesterase inhibitor aldicarb. mTDP-43 transgenics and unc-47 (e307) mutants were hypersensitive to aldicarb-induced paralysis compared with either wtTDP-43 transgenics or N2 worms (P < 0.001 for unc-47 [n = 61] or mTDP-43 [n = 67] compared with N2 [n = 69] or wtTDP-43 worms [n = 66]). Pimozide reduced the aldicarb-induced paralysis in mTDP-43 transgenics (n = 63) as well as unc-47 (e307) mutants (n = 74) (P < 0.001). To assess synaptic transmission across the NMJ in zebrafish models of ALS, paired recordings (primary motoneuron–muscle [MN-muscle]) were preformed. (B) Example traces of EPCs in fast-twitch muscles in wtTDP-43 and mutTDP-43 fish with and without pimozide were recorded following a 10-second train of depolarizing (action potential generating); current steps delivered at 30 Hz. Pimozide treatment was found to recover the fidelity of synaptic transmission (C), the EPC amplitude (D) and the coefficient of variation (E) in mTDP-43 fish (n = 10). Data are represented as mean±SEM. Significance was determined using one-way ANOVA and Fisher LSD tests for normally distributed and equal variance data, Kruskal-Wallis ANOVA and Dunn’s method of comparison were used for nonnormal distributions.
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