Invited reviewModels of hyperkinetic disorders in primates
Introduction
Hyperkinetic movement disorders include tremors, dystonia, chorea, tics, myoclonus, stereotypies, restless legs syndrome, and various other disorders with abnormal involuntary movements. Although a number of disorders could be included in such a broad spectrum, a limited number of conditions are modeled in non-human primates (NHPs). These conditions include notably L-dopa-induced dyskinesia (LID) in Parkinson’s disease (PD), tardive dyskinesia (TD), essential tremor (ET) and Huntington’s disease (HD). NHP models of these conditions exist. They were or are currently in use in a limited number of laboratories throughout the world. Although the translational value of NHP in neurological research is widely acknowledged, the field is everywhere submitted to non-scientific concerns and hence pressure towards diminishing their use, thereby actually limiting the number of teams achieving top-notch science in these species. Moving away from such valuable models would however ultimately jeopardize our capability to develop effective treatments for the neurological conditions of concern, would we be left with the sole rodent models whose brain physiology and anatomy are in nature different from the one of primate lineage to which human beings belong. This short opiniated review surveys the current state of use of these models as well as the future developments.
Section snippets
Primate models of L-DOPA induced dyskinesia in Parkinson disease
Searching for therapeutic solutions has fuelled the search for valid translational experimental NHP models of the L-dopa-induced side effects in animals. Modeling LID in NHPs became possible because of the development of the now gold-standard model of parkinsonism obtained by exposure to the toxin MPTP. MPTP is a neurotoxin that induces a form of parkinsonism in humans which is indistinguishable from idiopathic PD (Langston et al., 1983). Primates exposed to MPTP show most of the motor problems
Primate model of tardive dyskinesia
Tardive dyskinesia (TD) is a disabling motor complication encompassing all persistent, abnormal, involuntary hyperkinetic movements occurring in the setting of chronic therapy with dopamine receptor-blocking agents, such as antipsychotic drugs (Blanchet, 2003). Although of relatively high prevalence with old anti-psychotics, developing NHP models of this debilitating complication has remained challenging over the years (Blanchet et al., 2012), notably characterized by the instability of the
Primate model of essential tremor
Although ET is the most common movement disorder, its pathophysiology remains elusive despite early attempts to decipher its pathophysiology. The field has however clearly not yet benefited from the progress in physiology and in molecular neuroscience as it should have and so are as well the NHP models of ET. A classical NHP model (rodent as well) of ET is the harmaline- induced model, promoting the concept that the action tremor induced by harmaline treatment through enhancing the coupling
Primate model of Huntington disease
Contrary to the three other conditions presented in this short review, HD, a rare monogenic autosomal dominant inherited fatal disease, is subject to an intense, although mainly technological, research in NHP because of the apparent simplicity of its cause (Aron Badin, 2018). Phenotypic models have been first developed while pathocopies are now being proposed thanks to the progress of genetic engineering for which HD has become a school case (Yang et al., 2008). Neurotoxins, i.e. excitotoxic
Considerations for the use of primate in translational research
This author strongly supports the need of NHPs in Neuroscience on the ground that it is indispensable to the translation of knowledge to the human brain (Roelfsema and Treue, 2014), despite the obvious challenges faced by basic and applied scientific researchers, such as expense and technical expertise. While this may be reflected in the relative number of monkeys used for research compared to other species like rodents (0.1 % vs. 80 %, respectively) (Roelfsema and Treue, 2014), NHPs remain
Concluding remarks
NHP models of hyperkinetic movement disorders have been developed for L-dopa-induced dyskinesia in Parkinson’s disease, tardive dyskinesia, essential tremor and Huntington’s disease. Heuristic, predictive and hence translational phenocopic NHP models exist for the symptomatic management of L-dopa-induced dyskinesia in Parkinson’s disease and Huntington’s disease. Validating pathocopies of these hyperkinetic disorders is now required for hoping to develop disease-modifying strategies.
Acknowledgments
This review was supported by INSERM, CNRS and University of Bordeaux, France. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This review did not intend to be exhaustive and only reflect the opinion of the author.
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