Probenecid potentiates MPTP/MPP+ toxicity by interference with cellular energy metabolism

Authors

  • Daniel Alvarez-Fischer,

    1. UPMC Univ Paris 06, UMR_S 975 - UMR 7725, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    2. Inserm U 975, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    3. CNRS, UMR 7225, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    4. ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    5. Department of Neurology, Philipps-University Marburg, Marburg, Germany
    6. Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
    7. Department of Psychiatry, University of Lübeck, Lübeck, Germany
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  • Carmen Noelker,

    1. UPMC Univ Paris 06, UMR_S 975 - UMR 7725, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    2. Inserm U 975, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    3. CNRS, UMR 7225, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    4. ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    5. Department of Neurology, Philipps-University Marburg, Marburg, Germany
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  • Anne Grünewald,

    1. Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
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  • Franca Vulinović,

    1. Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
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  • Serge Guerreiro,

    1. UPMC Univ Paris 06, UMR_S 975 - UMR 7725, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    2. Inserm U 975, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    3. CNRS, UMR 7225, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    4. ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
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  • Julia Fuchs,

    1. Collège de France, Center for Interdisciplinary Research in Biology (CIRB), CNRS UMR 7241/INSERM U1050, Paris, France
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  • Lixia Lu,

    1. UPMC Univ Paris 06, UMR_S 975 - UMR 7725, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    2. Inserm U 975, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    3. CNRS, UMR 7225, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    4. ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    5. Department of Neurology, Philipps-University Marburg, Marburg, Germany
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  • Anne Lombès,

    1. Institut Cochin, INSERM UMRS 1016; CNRS UMR 8104, Université Paris Descartes, Paris, France
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  • Etienne C. Hirsch,

    1. UPMC Univ Paris 06, UMR_S 975 - UMR 7725, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    2. Inserm U 975, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    3. CNRS, UMR 7225, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    4. ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
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  • Wolfgang H. Oertel,

    1. Department of Neurology, Philipps-University Marburg, Marburg, Germany
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  • Patrick P. Michel,

    1. UPMC Univ Paris 06, UMR_S 975 - UMR 7725, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    2. Inserm U 975, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    3. CNRS, UMR 7225, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    4. ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
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  • Andreas Hartmann

    Corresponding author
    1. UPMC Univ Paris 06, UMR_S 975 - UMR 7725, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    2. Inserm U 975, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    3. CNRS, UMR 7225, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    4. ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France
    5. Department of Neurology, Philipps-University Marburg, Marburg, Germany
    6. Département de Neurologie, Pôle des Maladies du Système Nerveux, Hôpital de la Pitié-Salpêtrière, Paris, France
    • Address correspondence and reprint requests to Andreas Hartmann, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, UPMC/INSERM UMR_S975, Groupe Hospitalier Pitié-Salpêtrière, 47 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France. E-mail: andreas.hartmann@psl.aphp.fr

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Abstract

The uricosuric agent probenecid is co-administered with the dopaminergic neurotoxin MPTP to produce a chronic mouse model of Parkinson's disease. It has been proposed that probenecid serves to elevate concentrations of MPTP in the brain by reducing renal elimination of the toxin. However, this mechanism has never been formally demonstrated to date and is questioned by our previous data showing that intracerebral concentrations of MPP+, the active metabolite of MPTP, are not modified by co-injection of probenecid. In this study, we investigated the potentiating effects of probenecid in vivo and in vitro arguing against the possibility of altered metabolism or impaired renal elimination of MPTP. We find that probenecid (i) is toxic in itself to several neuronal populations apart from dopaminergic neurons, and (ii) that it also potentiates the effects of other mitochondrial complex I inhibitors such as rotenone. On a mechanistic level, we show that probenecid is able to lower intracellular ATP concentrations and that its toxic action on neuronal cells can be reversed by extracellular ATP. Probenecid can potentiate the effect of mitochondrial toxins due to its impact on ATP metabolism and could therefore be useful to model atypical parkinsonian syndromes.

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