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Deuterium-substituted l-DOPA displays increased behavioral potency and dopamine output in an animal model of Parkinson’s disease: comparison with the effects produced by l-DOPA and an MAO-B inhibitor

  • Neurology and Preclinical Neurological Studies - Original Article
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Abstract

The most effective treatment of Parkinson’s disease (PD) l-DOPA is associated with major side effects, in particular l-DOPA-induced dyskinesia, which motivates development of new treatment strategies. We have previously shown that chronic treatment with a substantially lower dose of deuterium-substituted l-DOPA (D3-l-DOPA), compared with l-DOPA, produced equal anti-parkinsonian effect and reduced dyskinesia in 6-OHDA-lesioned rats. The advantageous effects of D3-l-DOPA are in all probability related to a reduced metabolism of deuterium dopamine by the enzyme monoamine oxidase (MAO). Therefore, a comparative neurochemical analysis was here performed studying the effects of D3-l-DOPA and l-DOPA on dopamine output and metabolism in 6-OHDA-lesioned animals using in vivo microdialysis. The effects produced by D3-l-DOPA and l-DOPA alone were additionally compared with those elicited when the drugs were combined with the MAO-B inhibitor selegiline, used in PD treatment. The different treatment combinations were first evaluated for motor activation; here the increased potency of D3-l-DOPA, as compared to that of l-DOPA, was confirmed and shown to be of equal magnitude as the effect produced by the combination of selegiline/l-DOPA. The extracellular levels of dopamine were also increased following both D3-l-DOPA and selegiline/l-DOPA administration compared with l-DOPA administration. The enhanced behavioral and neurochemical effects produced by D3-l-DOPA and the combination of selegiline/l-DOPA are attributed to decreased metabolism of released dopamine by MAO-B. The similar effect produced by D3-l-DOPA and selegiline/l-DOPA, respectively, is of considerable clinical interest since D3-l-DOPA, previously shown to exhibit a wider therapeutic window, in addition may reduce the need for adjuvant MAO-B inhibitor treatment.

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Abbreviations

D3-l-DOPA:

Deuterium-substituted l-DOPA

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Acknowledgements

We thank Mrs. Anna Malmerfelt for excellent technical assistance. This study was supported by the Swedish Research Council (Grant No. 4747), the Swedish Parkinson´s disease Association, the Swedish Brain Foundation, the Lars Hierta Foundation and Karolinska Institutet. BiRDS Pharma GmbH, has partly supported this study by a research grant to the Karolinska Institutet.

Conflict of interest

RG. Alken and F. Schneider are both scientists supported by BiRDs Pharma GmbH (part of the BDD/CDRD Group), the manufacturers of D3-l-DOPA. T H. Svensson has received research grants from AstraZeneca, Organon, Schering-Plough, Merck and Johnson & Johnson and has served at AstraZeneca and Lundbeck scientific advisory board meetings. T. Malmlöf, K. Feltmann, Å. Konradsson-Geuken and B. Schilström declare that, except for income received from our universities, no financial support or compensation has been received over the past 3 years for research or professional service that within this context could be considered as constituting a potential conflict of interest.

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  1. Section of Neuropsychopharmacology, Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, 171 77, Stockholm, Sweden

    Torun Malmlöf, Kristin Feltmann, Åsa Konradsson-Geuken, Torgny H. Svensson & Björn Schilström

  2. CDRD Berolina AB, Fontanestraße 84-90, D-15366, Neuenhagen, Germany

    Frank Schneider

  3. BiRDS Pharma GmbH, Fontanestraße 84-90, D-15366, Neuenhagen, Germany

    Rudolf-Giesbert Alken

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  1. Torun Malmlöf
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Malmlöf, T., Feltmann, K., Konradsson-Geuken, Å. et al. Deuterium-substituted l-DOPA displays increased behavioral potency and dopamine output in an animal model of Parkinson’s disease: comparison with the effects produced by l-DOPA and an MAO-B inhibitor. J Neural Transm 122, 259–272 (2015). https://doi.org/10.1007/s00702-014-1247-6

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