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MPTP toxicity in rat striatal slices: dopamine uptake alteration does not appear to be related to lipid peroxidation
Abstract:
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is used to create experimental models of parkinsonism, induces both dopaminergic neurotoxicity and peroxidation reactions. The present work investigated the interaction between the dopamine (DA) uptake system, lipid peroxidation and MPTP in a rat striatum slice model. [3H]DA uptake was decreased and the concentration of thiobarbituric acid reactive substances (TBARS) increased after a plain preincubation in Krebs-Ringer bicarbonate buffer for 150 min. The decrease in [3H]DA uptake and the increase in TBARS were suppressed by the iron-chelating agent desferrioxamine. Inhibition of [3H]DA uptake was intensified, [3H]GBR 12 935 binding to DA uptake sites was decreased and TBARS production was inhibited in slices after preincubation with MPTP. MPTP effects were inhibited by L-deprenyl, a MAO-B inhibitor. These results suggest that the spontaneous decrease in DA uptake during simple preincubation in pure Krebs-Ringer solution was related to spontaneous TBARS generation. During MPTP preincubation, alteration of the DA uptake mechanism was not due to additional lipid peroxidation since TBARS production was decreased. MPTP effects could have resulted from other events which are discussed.
Insights
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism by affecting dopamine uptake. This study shows MPTP alters dopamine uptake mechanisms, not solely through lipid peroxidation, suggesting other pathways are involved.
Area of Science:
- Neuroscience
- Neuropharmacology
- Biochemistry
Background:
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin used to model parkinsonism.
- MPTP induces dopaminergic neurotoxicity and lipid peroxidation.
Purpose of the Study:
- Investigate the interaction between dopamine (DA) uptake, lipid peroxidation, and MPTP in a rat striatum slice model.
- Clarify the mechanisms underlying MPTP-induced neurotoxicity.
Main Methods:
- Utilized rat striatum slices.
- Measured [3H]DA uptake and thiobarbituric acid reactive substances (TBARS) as indicators of lipid peroxidation.
- Preincubated slices with and without MPTP, desferrioxamine (iron chelator), and L-deprenyl (MAO-B inhibitor).
- Assessed [3H]GBR 12 935 binding to DA uptake sites.
Main Results:
- Spontaneous preincubation decreased [3H]DA uptake and increased TBARS, effects suppressed by desferrioxamine.
- MPTP preincubation intensified [3H]DA uptake inhibition, decreased [3H]GBR 12 935 binding, and inhibited TBARS production.
- MPTP effects were counteracted by L-deprenyl.
Conclusions:
- Spontaneous DA uptake reduction in vitro is linked to lipid peroxidation.
- MPTP-induced alterations in DA uptake are not solely due to increased lipid peroxidation, as TBARS production decreased.
- MPTP's neurotoxic effects likely involve mechanisms beyond direct lipid peroxidation.