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

Abstract

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.Electronic supplementary materialThe online version of this article (10.1007/s13311-018-0634-3) contains supplementary material, which is available to authorized users.

The Peripheral Nervous System in Amyotrophic Lateral Sclerosis: Opportunities for Translational Research

“…A drug-screening platform in C. elegans and zebrafish models of ALS identified pimozide, an already approved neuroleptic, as a NMJ stabilizer by blocking T-type Ca 2+ channels (Patten et al, 2017). Despite some benefits in neurophysiologic measures were reported in hSOD-1 G93A mice and human patients in the first report, one study assessing long-term effects showed warned caution, as worsening of survival and muscle function were observed in mutant SOD1, and TDP-43 mice models (Pozzi et al, 2018). Notably, an agonist antibody directed toward muscle-specific kinase (MuSK), a post-synaptic tyrosine kinase receptor essential for NMJ maintenance, preserved motor synapses, delayed muscle denervation and extended lifespan in hSOD-1 G93A ALS mice (Cantor et al, 2018).…”

Disease-modifying therapies in amyotrophic lateral sclerosis

“…It has also enhancing effects on the neuromuscular transmission in ALS (Patten et al, 2017). Although not effective in two mouse models of ALS (Pozzi et al, 2018), pimozide is investigated in ALS in a placebo-controlled phase 2 trial (NCT03272503).…”

In a search for efficient treatment for amyotrophic lateral sclerosis: Old drugs for new approaches

“…Unexpectedly, pimozide aggravated pathology in both models. Significant increase of pathogenic protein aggregate accumulation in the nervous system, worsening of the neuromuscular connectivity and consecutively, motor functions and reduced lifespan were observed for pimozide‐treated compared with vehicle‐treated animals 38 . Reasons for a damaging effect of chronic pimozide treatment on mouse models of ALS pathology are not clear but these latest observations cast doubts on the future of this drug for ALS treatment.…”