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Striatal MPP+ levels do not necessarily correlate with striatal dopamine levels after MPTP treatment in mice
F Vaglini1, F Fascetti, D Tedeschi
1Institute of Pharmacology, School of Medicine, University of Pisa, Italy.
Abstract:
The present study offers confirmation of the fact that an MAO-B inhibitor, (-) deprenyl and a DA uptake blocker, GBR-12909, prevent MPTP-induced striatal DA decrease. This protective effect is accompanied by an almost complete prevention of MPP+ production induced by (-) deprenyl and an accelerated MPP+ clearance induced by GBR-12909 within the striatum. Similarly, the MPTP toxicity enhancers, DDC and acetaldehyde, both increase striatal MPP+ levels, as previously reported. On the contrary, the treatment with MK 801, although uneffective in preventing the long-term MPTP-induced striatal DA decrease, causes an increase in the striatal amount of MPP+. In a similar way, the administration of nicotine in combination with MPTP produces a significant increase in the levels of striatal MPP+, which does not elicit any effect on striatal DA. The effect of clonidine is consistent with these results and in sharp contrast with the current belief that a direct relationship exists between striatal MPP+ concentrations and the degree of MPTP-induced depletion of striatal DA. In this study, using different treatments, we failed to confirm the correlation between MPP+ striatal levels and dopaminergic lesions after MPTP administration in mice. We suggest that this correlation is not a rule and exceptions may depend on a different compartimentalization of the toxic metabolite.
Insights
MPTP-induced neurotoxicity in mice is complex. This study found no direct correlation between striatal MPP+ levels and dopaminergic damage, suggesting compartmentalization influences toxicity.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin that causes Parkinsonism.
- MPTP is metabolized to MPP+ (1-methyl-4-phenylpyridinium), which is toxic to dopaminergic neurons.
- The relationship between MPP+ levels and dopaminergic neuron loss is not fully understood.
Purpose of the Study:
- To investigate the relationship between striatal MPP+ levels and MPTP-induced dopaminergic neurotoxicity.
- To examine the effects of various agents on MPTP neurotoxicity and MPP+ levels.
Main Methods:
- Mice were treated with MPTP alone or in combination with MAO-B inhibitor (-)-deprenyl, DA uptake blocker GBR-12909, NMDA antagonist MK-801, nicotine, or clonidine.
- Striatal dopamine levels and MPP+ concentrations were measured.
Main Results:
- (-)-Deprenyl and GBR-12909 protected against MPTP-induced striatal dopamine decrease, with (-)-deprenyl preventing MPP+ production and GBR-12909 accelerating MPP+ clearance.
- MK-801, nicotine, and clonidine increased striatal MPP+ levels but did not prevent dopaminergic depletion, challenging the direct correlation hypothesis.
- DDC and acetaldehyde enhanced MPTP toxicity by increasing striatal MPP+ levels.
Conclusions:
- The correlation between striatal MPP+ levels and the extent of MPTP-induced dopaminergic lesions is not absolute.
- Compartmentalization of MPP+ within the striatum may explain discrepancies between MPP+ levels and neurotoxicity.