Elsevier

Neuroscience

Volume 106, Issue 3, 27 September 2001, Pages 589-601
Neuroscience

Mouse model of Parkinsonism: a comparison between subacute MPTP and chronic MPTP/probenecid treatment

https://doi.org/10.1016/S0306-4522(01)00295-0Get rights and content

Abstract

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is widely used to induce an animal model of Parkinsonism. The conventional mouse model, which usually involves acute or subacute injections of MPTP, results in a significant but reversible loss of dopaminergic functions. We have developed an alternative mouse model, in which co-administration of MPTP with probenecid results in the chronic loss of striatal dopamine for at least 6 months after cessation of treatment. In the present study, we compare the neurochemical, morphological and behavioral changes that occur in this alternative, chronic model with those in the conventional, subacute model. In the chronic model, we demonstrate an almost 80% loss of striatal dopamine and dopamine uptake 6 months after withdrawal from treatment. The neurochemical signs match unbiased stereological measures that demonstrate gradual loss of substantia nigra neurons. Rotarod performance further substantiates these findings by showing a progressive decline in motor performance.

Based on the comparisons made in this study in mice, the chronic MPTP/probenecid model shows considerable improvements over the conventional, subacute MPTP model. The sustained alterations in the nigrostriatal pathway resemble the cardinal signs of human Parkinson’s disease and suggest that this chronic mouse model is potentially useful to study the pathophysiology and mechanisms of Parkinsonism. It should also prove useful for the development of neuroprotection strategies.

Section snippets

Animals

Eight- to 10-week-old, male, C57BL/6 mice (Charles River Laboratories, Wilmington, MA, USA), weighing 22–25 g at the beginning of the study, were housed two to five animals per cage with food pellets and water available ad libitum. The room was maintained at constant temperature and humidity on a 12-h light–dark cycle. A minimum number of mice required to produce reliable scientific data was used in this study. All animal treatments including anesthesia were carried out strictly according to

Striatal dopamine levels

The striatal DA contents among respective control groups in subacute and chronic studies did not differ significantly and thus, data arising from animals in those groups were pooled. As shown in Fig. 1A, 3 days after the subacute MPTP treatment, the loss of striatal DA was highly significant (76% loss). Thirty days after the treatment, the loss of striatal DA remained significant but to a lesser extent (53% loss) when compared to controls, suggesting that a partial recovery had occurred.

Discussion

In order to identify the pathophysiological mechanisms of PD and to develop new strategies for neuroprotection, it is imperative to establish a long-term animal model that closely resembles human Parkinsonism. This report presents a close correlation between neurochemical, morphological and behavioral manifestations validating a new model of MPTP Parkinsonism in a single study. We provide evidence that, for 6 months after chronic MPTP/probenecid treatment, C57BL mice exhibit a marked depletion

Conclusion

We have shown that the chronic treatment of mice with MPTP/probenecid is accompanied by sustained nigrostriatal degeneration and motor decline resembling human PD. Based on the comparisons made in this study, this chronic model is an improvement over the conventional acute and subacute models. The chronic MPTP/probenecid model has a potential for explorations of disease progression, mechanisms of neurodegeneration, and neuroprotection.

Acknowledgements

The authors thank Dr. P.L. Gabbott for providing the StereoInvestigator apparatus and Charlie Callison, Katy Schafbuch and Shari Buzolich for their technical contributions to the work. This research was supported in part by grants from the University of Missouri Research Board, the Health Future Foundation, Inc., the National Parkinson Foundation, Inc. (to Y.-S.L.), and the National Institute of Neurological Disorders and Stroke (R01 NS41799 to G.E.M., Y.-S.L. and S.T.).

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