Community Action Needed: Please respond to the NIH RFI
ZFIN ID: ZDB-PUB-171205-12
Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis
Patten, S.A., Aggad, D., Martinez, J., Tremblay, E., Petrillo, J., Armstrong, G.A., La Fontaine, A., Maios, C., Liao, M., Ciura, S., Wen, X.Y., Rafuse, V., Ichida, J., Zinman, L., Julien, J.P., Kabashi, E., Robitaille, R., Korngut, L., Parker, J.A., Drapeau, P.
Date: 2017
Source: JCI insight   2(22): (Journal)
Registered Authors: Drapeau, Pierre, Patten, Shumoogum, Wen, Xiao-Yan
Keywords: ALS, Calcium channels, Clinical Trials, Neurodegeneration, Neuroscience
MeSH Terms:
  • Amyotrophic Lateral Sclerosis/drug therapy*
  • Animals
  • Antipsychotic Agents/pharmacokinetics*
  • Antipsychotic Agents/therapeutic use*
  • Caenorhabditis elegans
  • Calcium Channels/drug effects
  • Calcium Channels, T-Type/drug effects
  • DNA-Binding Proteins/metabolism
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Drug Tolerance
  • Female
  • Mice
  • Neuromuscular Junction/drug effects
  • Neuromuscular Junction Diseases/drug therapy*
  • Pimozide/pharmacology
  • Zebrafish
  • Zebrafish Proteins/metabolism
PubMed: 29202456 Full text @ JCI Insight
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.