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Study of the antidyskinetic effect of eltoprazine in animal models of levodopa-induced dyskinesia

Authors

  • Erwan Bezard PhD,

    1. Institute for Neurodegenerative Diseases, Bordeaux University, Bordeaux, France
    2. Institute for Neurodegenerative Diseases, National Center for Scientific Research, Bordeaux, France
    3. Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China
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  • Elisabetta Tronci PhD,

    1. Physiology Section, Department of Biomedical Sciences, Cagliari University, Cagliari, Italy
    2. Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden
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  • Elsa Y. Pioli PhD,

    1. Motac Neuroscience Ltd., Manchester, United Kingdom
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  • Qin Li PhD,

    1. Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China
    2. Motac Neuroscience Ltd., Manchester, United Kingdom
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  • Gregory Porras PhD,

    1. Motac Neuroscience Ltd., Manchester, United Kingdom
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  • Anders Björklund MD,

    1. Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden
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  • Manolo Carta PhD

    Corresponding author
    1. Physiology Section, Department of Biomedical Sciences, Cagliari University, Cagliari, Italy
    2. Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden
    • Correspondence to: Dr. Manolo Carta, Department of Biomedical Sciences, Section of Physiology, Cagliari University, University Campus, 09042 Monserrato, Italy; manolocarta@unica.it

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  • Funding agencies: This study was supported by a grant from the Michael J. Fox Foundation. E.B. was also supported by grants from the Agence Nationale de la Recherche, the China Science Fund, the Seventh Framework Programme (FP7 of the European Union, France Parkinson, Fondation de France, and the Cariplo Foundation.

  • Relevant conflicts of interest/financial disclosures: E.B. has an equity stake in Motac Holding Ltd. and receives consultancy payments from Motac Neuroscience Ltd. E.B., Q.L., and G.P. are employees of Motac Neuroscience Ltd.

  • Full financial disclosures and author roles may be found in the Acknowledgments section online.

Abstract

The serotonin (5-hydroxytryptamine [5HT]) system has recently emerged as an important player in the appearance of l-3,4-dihydroxyphenylalanine (levodopa [l-dopa])–induced dyskinesia in animal models of Parkinson's disease. In fact, dopamine released as a false transmitter from serotonin neurons appears to contribute to the pulsatile stimulation of dopamine receptors, leading to the appearance of the abnormal involuntary movements. Thus, drugs able to dampen the activity of serotonin neurons hold promise for the treatment of dyskinesia. The authors investigated the ability of the mixed 5-HT 1A/1B receptor agonist eltoprazine to counteract l-dopa–induced dyskinesia in 6-hydroxydopamine-lesioned rats and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques. The data demonstrated that eltoprazine is extremely effective in suppressing dyskinesia in experimental models, although this effect was accompanied by a partial worsening of the therapeutic effect of l-dopa. Interestingly, eltoprazine was found to (synergistically) potentiate the antidyskinetic effect of amantadine. The current data indicated that eltoprazine is highly effective in counteracting dyskinesia in preclinical models. However, the partial worsening of the l-dopa effect observed after eltoprazine administration represents a concern; whether this side effect is due to a limitation of the animal models or to an intrinsic property of eltoprazine needs to be addressed in ongoing clinical trials. The data also suggest that the combination of low doses of eltoprazine with amantadine may represent a valid strategy to increase the antidyskinetic effect and reduce the eltoprazine-induced worsening of l-dopa therapeutic effects. © 2013 Movement Disorder Society

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