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MPP+-induced pathophysiology demonstrates advantages of neurotoxicology studies in brain slices
G E Hollinden1, J R Sanchez-Ramos, T J Sick
1Department of Neurology, University of Miami School of Medicine, FL 33101.
Abstract:
Since MPTP and its metabolite MPP+ produce nigrostriatal lesions and symptoms similar to Parkinson's disease, recent studies have aimed toward defining their selectivity and neurotoxic mechanisms. In mitochondria in vitro, MPP+ blocked electron transport and decreased oxygen consumption. However, these effects were not selective to striatal mitochondria or even to mitochondria from brain, they required concentrations of MPP+ much greater than those found in vivo, and physiological actions could not be related to intramitochondrial changes. Lower doses of MPP+ did produce highly selective degeneration of dopaminergic (DA) neurons in cell cultures. We report here that MPP+ provoked large (80%) oxidations of cytochrome b and large K+o increments (approximately 30 mM) in rat striatal slices. These effects were slowed by mazindol, which inhibits DA uptake, and were markedly attenuated in rat hippocampal slices which have little DA input. Since DA terminals comprise only 2-4% of the striatal mass, the large MPP+-induced changes suggest that while MPP+ neurotoxicity in brain requires the presence of functioning DA terminals, effects are not confined to these terminals. Such studies illustrate the complexity of MPP+ neurotoxicity and demonstrate the importance of investigations in models such as brain slices with an extracellular space and intracellular relationships as in intact brain.
Insights
MPP+ causes significant changes in brain slices, suggesting its neurotoxicity involves more than just dopaminergic neurons. These findings highlight the complexity of MPP+ effects in models resembling the intact brain.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- MPTP and its metabolite MPP+ induce Parkinson's-like symptoms.
- Previous in vitro studies showed MPP+ inhibits mitochondrial function but lacked selectivity.
- Lower MPP+ doses selectively damage dopaminergic neurons in cell cultures.
Purpose of the Study:
- To investigate the neurotoxic mechanisms and selectivity of MPP+ in brain slices.
- To understand MPP+ effects in a more physiologically relevant model than isolated mitochondria or cell cultures.
Main Methods:
- Utilized rat striatal and hippocampal slices.
- Measured cytochrome b oxidation and extracellular potassium (K+o) changes.
- Investigated the role of dopamine (DA) uptake using mazindol.
Main Results:
- MPP+ caused substantial cytochrome b oxidation and K+o increments in striatal slices.
- These effects were dependent on DA uptake, as indicated by mazindol's inhibitory action.
- MPP+-induced changes were less pronounced in hippocampal slices with lower DA input.
- Despite DA terminals being a small fraction of striatal mass, MPP+ effects were widespread.
Conclusions:
- MPP+ neurotoxicity in brain slices requires functional dopaminergic terminals.
- The observed effects extend beyond dopaminergic terminals, indicating broader cellular impact.
- Brain slice models are crucial for understanding complex neurotoxic mechanisms of MPP+ in vivo.