Abstract
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model remains the most commonly used animal model of Parkinson's disease (PD). There are three MPTP-treatment schemes: acute, subacute and chronic. Considering the advantages of the period and similarity to PD, the subacute model was often chosen to assess the validity of new candidates, but the changes caused by the subacute MPTP treatment and the appropriate positive control for this model remain to be further confirmed. The aim of this study was: to estimate the value of the subacute MPTP mouse model in aspects of behavioral performance, biochemical changes and pathological abnormalities, and to find effective positive drugs. Male C57BL/6 mice were injected with MPTP (30 mg·kg−1·d−1, ip) for 5 consecutive days. Three days before MPTP injection, the mice were orally administered selegiline (3 mg·kg−1·d−1), pramipexole (3 mg·kg−1·d−1), or medopar (100 mg·kg−1·d−1) for 18 days. Behavioral performance was assessed in the open field test, pole test and rotarod test. Neurotransmitters in the striatum were detected using HPLC. Protein levels were measured by Western blot. Pathological characteristics were examined by immunohistochemistry. Ultrastructure changes were observed by electron microscopy. The subacute MPTP treatment did not induce evident motor defects despite severe injuries in the dopaminergic system. Additionally, MPTP significantly increased the α-synuclein levels and the number of astrocytes in the striatum, and destroyed the blood-brain barrier (BBB) in the substantia nigra pars compacta. Both selegiline and pramipexole were able to protect the mice against MPTP injuries. We conclude that the subacute MPTP mouse model does not show visible motor defects; it is not enough to evaluate the validity of a candidate just based on behavioral examination, much attention should also be paid to the alterations in neurotransmitters, astrocytes, α-synuclein and the BBB. In addition, selegiline or pramipexole is a better choice than medopar as an effective positive control for the subacute MPTP model.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (No 81373997, U1402221, 81573640, 81603316), Beijing Natural Science Foundation (No 7161011), the Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (No BZ0150), CAMS Innovation Fund for Medical Sciences (CIFMS) (No 2016-I2M-1-004), Key Research and Development Project of Hunan Province (No 2015SK2029-1), and the Scientific Research Foundation of the Higher Education Institutions of Hunan Province (No 15K091).
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Zhang, Qs., Heng, Y., Mou, Z. et al. Reassessment of subacute MPTP-treated mice as animal model of Parkinson's disease. Acta Pharmacol Sin 38, 1317–1328 (2017). https://doi.org/10.1038/aps.2017.49
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DOI: https://doi.org/10.1038/aps.2017.49
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