1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) decreases glutamate uptake in cultured astrocytes

Alan S. Hazell, Yossef Itzhak, Huaping Liu, Michael D. Norenberg

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

The deleterious effect of the parkinsonian neurotoxin 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP) on dopaminergic neurons of the substantia nigra is well established. In addition, increased glutamatergic drive to basal ganglia output nuclei is considered a likely contributor to the pathogenesis of Parkinson's disease. One possibility for the increased excitatory tone may be related to an impairment in glutamate uptake. As astrocytes possess efficient transport mechanisms for both MPTP and glutamate, we have examined the effect of this agent on D-aspartate uptake into these cells. Treatment of cultures with 50 μM MPTP for 24 h decreased uptake by 39%. Kinetic analysis revealed that this effect was due to a 35% decrease in V(max) with no change in the K(m). Treatment with deprenyl, a monoamine oxidase B inhibitor, produced a complete reversal of MPTP-induced uptake inhibition, but was ineffective following exposure of cells to the MPTP metabolite, 1-methyl-4-phenylpyridinium (MPP+). Removal of MPTP from cultures resulted in a complete restoration of glutamate uptake after 24 h. These results show that MPTP reversibly compromises glutamate uptake in cultured astrocytes, which is dependent on the conversion of MPTP to MPP+. Such findings suggest that the glutamate transporter in astrocytes plays an important role in MPTP-induced neurotoxicity and possibly in parkinsonism.

Original languageEnglish (US)
Pages (from-to)2216-2219
Number of pages4
JournalJournal of neurochemistry
Volume68
Issue number5
DOIs
StatePublished - May 1997

Keywords

  • 1-Methyl-4-phenyl-l,2,3,6- tetrahydropyridine
  • Astrocytes
  • Glutamate transport
  • Parkinson's disease

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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