Predictive Value of Parkinsonian Primates in Pharmacologic Studies: A Comparison between the Macaque, Marmoset, and Squirrel Monkey

Abstract

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate is the gold-standard animal model of Parkinson disease (PD) and has been used to assess the effectiveness of experimental drugs on dyskinesia, parkinsonism, and psychosis. Three species have been used in most studies-the macaque, marmoset, and squirrel monkey-the last much less so than the first two species; however, the predictive value of each species at forecasting clinical efficacy, or lack thereof, is poorly documented. Here, we have reviewed all the published literature detailing pharmacologic studies that assessed the effects of experimental drugs on dyskinesia, parkinsonism, and psychosis in each of these species and have calculated their predictive value of success and failure at the clinical level. We found that, for dyskinesia, the macaque has a positive predictive value of 87.5% and a false-positive rate of 38.1%, whereas the marmoset has a positive predictive value of 76.9% and a false-positive rate of 15.6%. For parkinsonism, the macaque has a positive predictive value of 68.2% and a false-positive rate of 44.4%, whereas the marmoset has a positive predictive value of 86.9% and a false-positive rate of 41.7%. No drug that alleviates psychosis in the clinic has shown efficacy at doing so in the macaque, whereas the marmoset has 100% positive predictive value. The small number of studies conducted in the squirrel monkey precluded us from calculating its predictive efficacy. We hope our results will help in the design of pharmacologic experiments and will facilitate the drug discovery and development process in PD.

The 5‐HT2A/2C inverse agonist nelotanserin alleviates L‐DOPA‐induced dyskinesia in the MPTP‐lesioned marmoset

“…We undertook the current study to investigate whether nelotanserin would alleviate L‐DOPA‐induced dyskinesia in the MPTP‐lesioned marmoset to provide incremental evidence of 5‐HT 2A antagonism/inverse agonism as an effective anti‐dyskinetic approach. As the marmoset has high predictive value of the efficacy of drugs at the phase II level (Beaudry & Huot, 2020; Veyres et al, 2018), if nelotanserin is demonstrated to be an efficacious anti‐dyskinetic molecule in this animal model of PD, it could conceivably be repurposed for the treatment of drug‐induced dyskinesia.…”

The Common Marmoset—Biomedical Research Animal Model Applications and Common Spontaneous Diseases

“…Over the past two decades, marmosets have been more frequently used in preclinical, toxicology, and safety assessment of drugs. 4-30…”

A Matrigel-based 3D construct of SH-SY5Y cells models the α-synuclein pathologies of Parkinson's disease

“…The capture of the multifactorial nature of PD is often difficult in cellular or animal models. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primate remains the gold-standard animal model of PD and is frequently used to evaluate the effectiveness of molecules on parkinsonism and psychosis ( Veyres et al, 2018 ). Higher MPTP dose can lead to acute dopaminergic cell loss within 1 month, while low dose usually takes 8-12 months to achieve stable parkinsonism ( Bezard et al, 2001 ; Seo et al, 2019 ; Barth et al, 2020 ).…”