Preferential Extracellular Generation of the Active Parkinsonian Toxin MPP+ by Transporter-Independent Export of the Intermediate MPDP+

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Antioxidants & Redox Signaling. 2015, 23(13), pp. 1001-1016. ISSN 1523-0864. eISSN 1557-7716. Available under: doi: 10.1089/ars.2015.6297
Zusammenfassung

Aims: 1-Methyl-4-phenyl-tetrahydropyridine (MPTP) is among the most widely used neurotoxins for inducing experimental parkinsonism. MPTP causes parkinsonian symptoms in mice, primates, and humans by killing a subpopulation of dopaminergic neurons. Extrapolations of data obtained using MPTP-based parkinsonism models to human disease are common; however, the precise mechanism by which MPTP is converted into its active neurotoxic metabolite, 1-methyl-4-phenyl-pyridinium (MPP+), has not been fully elucidated. In this study, we aimed to address two unanswered questions related to MPTP toxicology: (1) Why are MPTP-converting astrocytes largely spared from toxicity? (2) How does MPP+ reach the extracellular space?

Results: In MPTP-treated astrocytes, we discovered that the membrane-impermeable MPP+, which is generally assumed to be formed inside astrocytes, is almost exclusively detected outside of these cells. Instead of a transporter-mediated export, we found that the intermediate, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+), and/or its uncharged conjugate base passively diffused across cell membranes and that MPP+ was formed predominately by the extracellular oxidation of MPDP+ into MPP+. This nonenzymatic extracellular conversion of MPDP+ was promoted by O2, a more alkaline pH, and dopamine autoxidation products.

Innovation and Conclusion: Our data indicate that MPTP metabolism is compartmentalized between intracellular and extracellular environments, explain the absence of toxicity in MPTP-converting astrocytes, and provide a rationale for the preferential formation of MPP+ in the extracellular space. The mechanism of transporter-independent extracellular MPP+ formation described here indicates that extracellular genesis of MPP+ from MPDP is a necessary prerequisite for the selective uptake of this toxin by catecholaminergic neurons.

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ISO 690SCHILDKNECHT, Stefan, Regina PAPE, Johannes MEISER, Christiaan KARREMAN, Tobias STRITTMATTER, Meike ODERMATT, Erica CIRRI, Anke FRIEMEL, Markus RINGWALD, Noemi PASQUARELLI, Boris FERGER, Thomas BRUNNER, Andreas MARX, Heiko M. MÖLLER, Karsten HILLER, Marcel LEIST, 2015. Preferential Extracellular Generation of the Active Parkinsonian Toxin MPP+ by Transporter-Independent Export of the Intermediate MPDP+. In: Antioxidants & Redox Signaling. 2015, 23(13), pp. 1001-1016. ISSN 1523-0864. eISSN 1557-7716. Available under: doi: 10.1089/ars.2015.6297
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@article{Schildknecht2015-11-01Prefe-32160,
  year={2015},
  doi={10.1089/ars.2015.6297},
  title={Preferential Extracellular Generation of the Active Parkinsonian Toxin MPP<sup>+</sup> by Transporter-Independent Export of the Intermediate MPDP<sup>+</sup>},
  number={13},
  volume={23},
  issn={1523-0864},
  journal={Antioxidants & Redox Signaling},
  pages={1001--1016},
  author={Schildknecht, Stefan and Pape, Regina and Meiser, Johannes and Karreman, Christiaan and Strittmatter, Tobias and Odermatt, Meike and Cirri, Erica and Friemel, Anke and Ringwald, Markus and Pasquarelli, Noemi and Ferger, Boris and Brunner, Thomas and Marx, Andreas and Möller, Heiko M. and Hiller, Karsten and Leist, Marcel}
}
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    <dcterms:abstract xml:lang="eng">Aims: 1-Methyl-4-phenyl-tetrahydropyridine (MPTP) is among the most widely used neurotoxins for inducing experimental parkinsonism. MPTP causes parkinsonian symptoms in mice, primates, and humans by killing a subpopulation of dopaminergic neurons. Extrapolations of data obtained using MPTP-based parkinsonism models to human disease are common; however, the precise mechanism by which MPTP is converted into its active neurotoxic metabolite, 1-methyl-4-phenyl-pyridinium (MPP&lt;sup&gt;+&lt;/sup&gt;), has not been fully elucidated. In this study, we aimed to address two unanswered questions related to MPTP toxicology: (1) Why are MPTP-converting astrocytes largely spared from toxicity? (2) How does MPP&lt;sup&gt;+&lt;/sup&gt; reach the extracellular space?&lt;br /&gt;&lt;br /&gt;Results: In MPTP-treated astrocytes, we discovered that the membrane-impermeable MPP&lt;sup&gt;+&lt;/sup&gt;, which is generally assumed to be formed inside astrocytes, is almost exclusively detected outside of these cells. Instead of a transporter-mediated export, we found that the intermediate, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP&lt;sup&gt;+&lt;/sup&gt;), and/or its uncharged conjugate base passively diffused across cell membranes and that MPP&lt;sup&gt;+&lt;/sup&gt; was formed predominately by the extracellular oxidation of MPDP&lt;sup&gt;+&lt;/sup&gt; into MPP&lt;sup&gt;+&lt;/sup&gt;. This nonenzymatic extracellular conversion of MPDP&lt;sup&gt;+&lt;/sup&gt; was promoted by O&lt;sub&gt;2&lt;/sub&gt;, a more alkaline pH, and dopamine autoxidation products.&lt;br /&gt;&lt;br /&gt;Innovation and Conclusion: Our data indicate that MPTP metabolism is compartmentalized between intracellular and extracellular environments, explain the absence of toxicity in MPTP-converting astrocytes, and provide a rationale for the preferential formation of MPP&lt;sup&gt;+&lt;/sup&gt; in the extracellular space. The mechanism of transporter-independent extracellular MPP&lt;sup&gt;+&lt;/sup&gt; formation described here indicates that extracellular genesis of MPP&lt;sup&gt;+&lt;/sup&gt; from MPDP is a necessary prerequisite for the selective uptake of this toxin by catecholaminergic neurons.</dcterms:abstract>
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