TY  - JOUR
A1  - Schildknecht, Stefan
A1  - Pape, Regina
A1  - Meiser, Johannes
A1  - Karreman, Christiaan
A1  - Strittmatter, Tobias
A1  - Odermatt, Meike
A1  - Cirri, Erica
A1  - Friemel, Anke
A1  - Ringwald, Markus
A1  - Pasquarelli, Noemi
A1  - Ferger, Boris
A1  - Brunner, Thomas
A1  - Marx, Andreas
A1  - Moeller, Heiko M.
A1  - Hiller, Karsten
A1  - Leist, Marcel
T1  - Preferential Extracellular Generation of the Active Parkinsonian Toxin MPP+ by Transporter-Independent Export of the Intermediate MPDP+
JF  - Antioxidants & redox signaling
N2  - 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 O-2, 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.
Y1  - 2015
U6  - https://doi.org/10.1089/ars.2015.6297
SN  - 1523-0864
SN  - 1557-7716
VL  - 23
IS  - 13
SP  - 1001
EP  - 1016
PB  - Liebert
CY  - New Rochelle
ER  -