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(+)MK-801 prevents the DDC-induced enhancement of MPTP toxicity in mice
F Vaglini1, F Fascetti, F Fornai
1Institute of Pharmacology, School of Medicine, University of Pisa, Italy.
Abstract:
In order to reach deeper insight into the mechanism of diethyldithiocarbamate (DDC)-induced enhancement of MPTP toxicity in mice, MK-801, a non-competitive antagonist of NMDA receptors, has been used as a tool to study the role of excitatory amino acids. In agreement with previous reports, (+)MK-801 did not significantly affect either striatal dopamine (DA) or tyrosine-hydroxylase (TH) activity in MPTP-treated animals. On the contrary (+)MK-801, but not (-)MK-801 significantly reduced the DDC + MPTP-induced fall in striatal DA and TH activity. A similar preventing effect on DA metabolites (DOPAC and HVA) and HVA/DA ratio was observed. The number of TH+ neurons in the substantia nigra (SN) of (+)MK-801-pretreated mice was not significantly different from that of control animals, indicating that this treatment specifically antagonized the extensive DDC-induced lesion of dopaminergic cell bodies in this brain area. (+)MK-801 treatment did not affect the DDC-induced changes of striatal MPP+ levels, suggesting that the observed antagonism of MK-801 against DDC is not due to MPP+ kinetic modifications. Pretreatment with the MAO-B inhibitor, L-deprenyl, or with the DA uptake blocker, GBR 12909, completely prevented the marked DA depletion elicited by DDC + MPTP within the striatum. Both treatments also protected from the fall in DA metabolites and TH activity as well. This indicates that DDC-induced potentiation is dependent upon MPP+ production and its uptake by the dopaminergic nerve terminals. All these findings suggest that NMDA receptors play a crucial role in the DDC-induced enhancement of MPTP toxicity.
Insights
Diethyldithiocarbamate (DDC) enhances MPTP toxicity, but NMDA receptor antagonist MK-801 prevents this effect by protecting dopaminergic neurons. This suggests a crucial role for NMDA receptors in DDC-induced MPTP toxicity potentiation.
Area of Science:
- Neuroscience
- Neuropharmacology
- Toxicology
Background:
- Diethyldithiocarbamate (DDC) is known to enhance the toxicity of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).
- The precise mechanism underlying this potentiation remains incompletely understood, particularly the involvement of excitatory amino acids.
Purpose of the Study:
- To investigate the role of NMDA receptors in the DDC-induced enhancement of MPTP toxicity in mice.
- To elucidate the neuroprotective mechanisms against DDC + MPTP neurotoxicity.
Main Methods:
- Administration of MPTP and DDC to mice, with or without pretreatment with MK-801 (an NMDA receptor antagonist).
- Measurement of striatal dopamine (DA) levels, tyrosine-hydroxylase (TH) activity, and DA metabolites (DOPAC, HVA).
- Assessment of dopaminergic neuron survival in the substantia nigra (SN) and striatal MPP+ levels.
- Comparison with effects of L-deprenyl (MAO-B inhibitor) and GBR 12909 (DA uptake blocker).
Main Results:
- (+)MK-801 significantly reduced the DDC + MPTP-induced fall in striatal DA and TH activity, as well as DA metabolites.
- (+)MK-801 protected dopaminergic neurons in the SN from DDC-induced lesions without affecting MPP+ levels.
- L-deprenyl and GBR 12909 also prevented DA depletion, indicating the importance of MPP+ production and uptake.
Conclusions:
- NMDA receptors play a critical role in mediating the enhancement of MPTP toxicity by DDC.
- MK-801 exhibits neuroprotective effects against DDC-induced potentiation of MPTP neurotoxicity.
- The DDC-induced potentiation of MPTP toxicity is dependent on MPP+ formation and dopaminergic uptake, with NMDA receptor activation being a key contributing factor.
