Chronic Administration of Pimozide Fails to Attenuate Motor and Pathological Deficits in Two Mouse Models of Amyotrophic Lateral Sclerosis

Neurotherapeutics. 2018 Jul;15(3):715-727. doi: 10.1007/s13311-018-0634-3.


Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which presently does not have any efficient therapeutic approach. Pimozide, a Food and Drug Administration (FDA)-approved neuroepileptic drug, has been recently proposed as a promising treatment for ALS patients based on apparent stabilization of right hand muscles after a short-time administration. A new clinical trial started at the end of 2017 to recruit patients with a prolonged drug delivery schedule. Here, our aim was to investigate the effects of chronic administration of pimozide on disease progression and pathological events in two mouse models of ALS. Pimozide was administered every 2 days to transgenic mice bearing the ALS-linked A315T mutation on the human TAR DNA-binding protein 43 (TDP-43) gene and to mice carrying the human superoxide dismutase 1 (SOD1) gene with the ALS-linked G93A mutation. Chronic administration of pimozide exacerbated motor performances in both animal models and reduced survival in SOD1G93A mice. In TDP-43A315T, it decreased the percentage of innervated neuromuscular junctions (NMJs) and increased the accumulation of insoluble TDP-43. In SOD1G93A mice, pimozide had no effects on NMJ innervation or motoneuron loss, but it increased the levels of misfolded SOD1. We conclude that a chronic administration of pimozide did not confer beneficial effects on disease progression in two mouse models of ALS. In light of a new clinical trial on ALS patients with a chronic regime of pimozide, these results with mouse models suggest prudence and careful monitoring of ALS patients subjected to pimozide treatment.

Keywords: ALS; Pimozide; SOD1; TDP-43.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Age Factors
  • Amyotrophic Lateral Sclerosis / complications*
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • Anti-Dyskinesia Agents / administration & dosage*
  • Body Weight / drug effects
  • Body Weight / genetics
  • Botulinum Toxins, Type A / therapeutic use
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Movement Disorders / drug therapy*
  • Movement Disorders / etiology*
  • Muscle Strength / drug effects
  • Muscle Strength / genetics
  • Mutation / genetics
  • Neuromuscular Agents / therapeutic use
  • Neuromuscular Junction / drug effects
  • Neuromuscular Junction / pathology
  • Phosphopyruvate Hydratase / metabolism
  • Pimozide / adverse effects*
  • Statistics, Nonparametric
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism


  • Anti-Dyskinesia Agents
  • DNA-Binding Proteins
  • Neuromuscular Agents
  • TARDBP protein, human
  • Pimozide
  • SOD1 G93A protein
  • Superoxide Dismutase
  • Botulinum Toxins, Type A
  • Phosphopyruvate Hydratase