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Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs

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  • A Corrigendum to this article was published on 12 October 2018

This article has been updated

Abstract

Existing therapeutic strategies for managing Parkinson disease (PD), which focus on addressing the loss of dopamine and dopaminergic function linked with degeneration of dopaminergic neurons, are limited by side effects and lack of long-term efficacy. In recent decades, research into PD pathophysiology and pharmacology has focused on understanding and tackling the neurodegenerative processes and symptomology of PD. In this Review, we discuss the challenges associated with the development of novel therapies for PD, highlighting emerging agents that aim to target cell death, as well as new targets offering a symptomatic approach to managing features and progression of the disease.

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Change history

  • 12 October 2018

    In the original version of Figure 3, a dopamine D2 receptor had been positioned incorrectly and has now been moved to the correct presynaptic position on the dopaminergic neurons projecting to the basal ganglia motor circuit. In addition, the two Figure 2 citations that appeared on page 14 were incorrect and have now been changed to Figure 3.

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Acknowledgements

D.C. thanks P. Hongaard for inspiring this Review.

Author information

Affiliations

  1. Prexton Therapeutics, Geneva, Switzerland.

    • Delphine Charvin
    •  & Rossella Medori
  2. Department of Neurology, University of South Florida, Tampa, FL, USA.

    • Robert A. Hauser
  3. Centre d'Investigation Clinique CIC1436, Services de Neurologie et de Pharmacologie Clinique, Réseau NS-PARK/FCRIN et Centre COEN NeuroToul, CHU de Toulouse, INSERM, University of Toulouse 3, Toulouse, France.

    • Olivier Rascol

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Competing interests

D.C. has received scientific grants from the Michael J. Fox Foundation (MJFF). D.C. and R.M. are members of the Management Team of Prexton Therapeutics. O.R. has received scientific grants from Agence Nationale de la Recherche, CHU de Toulouse, France-Parkinson, INSERM-DHOS Recherche Clinique Translationnelle, MJFF, Programme Hospitalier de Recherche Clinique and the European Commission (FP7, H2020). O.R. is a scientific adviser or consultant for AbbVie, Adamas Pharmaceuticals, Acorda Therapeutics, Addex Therapeutics, AlzProtect, ApoPharma, AstraZeneca, Bial, Biogen, Britannia, Clevexel, Cynapsus, INC Research, Lundbeck, Merck, MundiPharma, Neuroderm, Novartis, Oxford Biomedica, Parexel, Pfizer, Prexton Therapeutics, Quintiles, Sanofi, Servier, Teva, UCB, XenoPort and Zambon. R.A.H. reports consulting fees from Guidepoint Global, Gerson Lehrman Group, LCN Consulting, Putnam Associates, the National Parkinson Foundation, eResearch Technology, Inc., Lundbeck, Cynapsus, Sarepta Therapeutics, Adamas Pharmaceuticals, Neurocrine Biosciences, Back Bay Life Science, US WorldMeds, Biotie Therapies, MJFF, Neuropore Therapies, the US National Institutes of Health, Projects in Knowledge, Prexton Therapeutics, Acorda Therapeutics, Vista Research, LifeMax, Peerview Press, ClinicalMind Medical and Therapeutic Communications, Sunovion Pharmaceuticals, Inc., the Academy for Continued Healthcare Learning, Outcomes Insights, Expert Connect, HealthLogix, Teva, Cowen and Company, Pharma Two B, Ltd., Pfizer, RMEI Medical Education for Better Outcomes, ClearView Healthcare Partners, Health Advances, Kyowa Kirin Pharmaceutical Development, Ltd., Impax Laboratories, Quintiles, Pfizer, AbbVie, AstraZeneca, Eli Lilly & Company, Decision Resources Group, Seagrove Partners, LLC, Intec Pharma, Ltd., Schlesinger Associates, Huron Consulting Group, Pennside Partners, Bracket, Phase Five Communications, LCN Consulting and the Windrose Consulting Group.

Corresponding author

Correspondence to Delphine Charvin.

Glossary

Bradykinesia

Abnormal slowness of movement.

Autonomic dysfunction

Abnormal functioning of the autonomic nervous system, affecting the functioning of the heart, bladder, intestines, sweat glands, pupils and blood vessels. Examples include constipation, orthostatic hypotension, urinary incontinence and erectile dysfunction.

Synucleinopathy

A neurodegenerative disease characterized by an excessive accumulation of α-synuclein. Examples include PD, dementia with Lewy bodies and multiple system atrophy.

Dyskinesia

Abnormal involuntary movements. Levodopa-induced dyskinesia is associated with chronic levodopa treatment in patients with PD. It is characterized by hyperkinetic movements including chorea, athetosis and dystonia.

Dopamine dysregulation syndrome

Dysfunction of the reward system associated with long-term dopaminergic treatments. It is characterized by addictive behaviours and excessive use of dopaminergic medication, with patients taking quantities of medication well beyond the dose required to treat their motor disabilities.

Disease modification

Efficacy of a therapy in stopping, slowing or delaying disease progression, and therefore the clinical decline, through an effect on the underlying pathological process (either cellular protection or restoration of cellular function).

Unified Parkinson Disease Rating Scale

(UPDRS). Used to assess severity and impact of PD signs and symptoms. It is made up of sections (parts I–IV) assessing different aspects of the disease.

Methyl-4 phenyl 1,2,3,6 tetrahydropyridine

(MPTP). A neurotoxin that causes irreversible loss of dopamine neurons and parkinsonism in mice, monkeys and humans. The neurotoxicity of MPTP was first discovered when a young man self-injected an illicit narcotic (desmethylprodine (MPPP)) containing MPTP as a major impurity. He developed PD motor symptoms and responded to levodopa therapy, and the autopsy showed selective degeneration of dopaminergic neurons of the substantia nigra.

ON/OFF

Alternating periods of good (ON) and poor (OFF) control of motor symptoms by levodopa treatment. ON refers to time when medication is providing benefit with regard to mobility, slowness and stiffness. OFF refers to time when a medication's efficacy has worn off and is no longer providing benefit with regard to mobility, slowness and stiffness.

Type 2 diabetes mellitus

(T2DM). Type of diabetes that is characterized by insulin resistance in appropriate hepatic glucose production and impaired insulin secretion. Onset is usually after 40 years.

Allosteric modulators

Molecules that bind a site that is different from the binding site of the endogenous agonist. As modulators, they act only in presence of the endogenous agonist, either potentiating (PAM) or reducing (NAM) the receptor response.

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DOI

https://doi.org/10.1038/nrd.2018.136