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Molecular basis of dopamine replacement therapy and its side effects in Parkinson’s disease

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Abstract

There is currently no cure for Parkinson’s disease. The symptomatic therapeutic strategy essentially relies on dopamine replacement whose efficacy was demonstrated more than 50 years ago following the introduction of the dopamine precursor, levodopa. The spectacular antiparkinsonian effect of levodopa is, however, balanced by major limitations including the occurrence of motor complications related to its particular pharmacokinetic and pharmacodynamic properties. Other therapeutic strategies have thus been developed to overcome these problems such as the use of dopamine receptor agonists, dopamine metabolism inhibitors and non-dopaminergic drugs. Here we review the pharmacology and molecular mechanisms of dopamine replacement therapy in Parkinson’s disease, both at the presynaptic and postsynaptic levels. The perspectives in terms of novel drug development and prediction of drug response for a more personalised medicine will be discussed.

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Funding

The research leading to these results received funding from the programme ‘Investissements d’Avenir’ ANR-10-IAIHU-06 and from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115,568, resources of which comprise financial contributions from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution.

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Authors and Affiliations

  1. Sorbonne Université, UPMC Univ Paris 06, UMR S 1127, ICM, Hôpital Pitié-Salpêtrière, Paris, France

    Hana You, Louise-Laure Mariani, Graziella Mangone & Jean-Christophe Corvol

  2. INSERM, Unit 1127, CIC 1422, NS-PARK/FCRIN, Hôpital Pitié-Salpêtrière, Paris, France

    Hana You, Louise-Laure Mariani, Graziella Mangone, Delphine Le Febvre de Nailly & Jean-Christophe Corvol

  3. CNRS, Unit 7225, Hôpital Pitié-Salpêtrière, Paris, France

    Hana You, Louise-Laure Mariani, Graziella Mangone & Jean-Christophe Corvol

  4. Assistance Publique Hôpitaux de Paris, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, France

    Hana You, Louise-Laure Mariani, Graziella Mangone & Jean-Christophe Corvol

  5. Department of Neurology, University Hospital (Inselspital) and University of Bern, Freiburgstrasse 18, 3010, Bern, Switzerland

    Hana You

  6. Assistance Publique Hôpitaux de Paris, Department of Pharmacy, Hôpital Pitié-Salpêtrière, Paris, France

    Delphine Le Febvre de Nailly & Fanny Charbonnier-Beaupel

  7. CIC Neurosciences, ICM building, Hôpital Pitié-Salpêtrière, 47/83 Boulevard de l’Hôpital, 75013, Paris, France

    Jean-Christophe Corvol

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  1. Hana You
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  2. Louise-Laure Mariani
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Correspondence to Jean-Christophe Corvol.

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Conflicts of interest

J.C.C. is in receipt of research grants from the French Ministry of Health, Agence Nationale pour le Recherche, Michael J Fox Foundation and honoraria for scientific advice from BMS, Zambon, Pfizer, Ipsen, Abbvie, Amarantus, Clevexel unrelated to this work. L.L.M. has received research support grants from INSERM, JNLF, The L’Oreal Foundation; speech honoraria from CSL, Sanofi-Genzyme, Lundbeck Teva; and received travel funding from the Movement Disorders Society, ANAINF, Medtronic, Teva and AbbVie, outside the submitted work. H.Y., G.M., D.L.F.D.N. and F.C.B. have no conflict of interest.

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You, H., Mariani, LL., Mangone, G. et al. Molecular basis of dopamine replacement therapy and its side effects in Parkinson’s disease. Cell Tissue Res 373, 111–135 (2018). https://doi.org/10.1007/s00441-018-2813-2

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