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MPTP Mouse Model of Preclinical and Clinical Parkinson’s Disease as an Instrument for Translational Medicine

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Abstract

Parkinson’s disease (PD) is characterized by the appearance of motor symptoms many years after the onset of neurodegeneration, which explains low efficiency of therapy. Therefore, one of the priorities in neurology is to develop an early diagnosis and preventive treatment of PD, based on knowledge of molecular mechanisms of neurodegeneration and neuroplasticity in the nigrostriatal system. However, due to inability to diagnose PD at preclinical stage, research and development must be performed in animal models by comparing the nigrostriatal system in the models of asymptomatic and early symptomatic stages of PD. In this study, we showed that despite the progressive loss of neurons in the substantia nigra at the presymptomatic and symptomatic stage, almost no change was observed in the main functional characteristics of this brain region, including dopamine (DA) uptake and release, dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) expression, and activity of MAO-A and MAO-B. In the striatum of presymptomatic mice, some parameters (DA release and uptake, MAO-A activity) remained compensatory unchanged or compensatory decreased (MAO-B gene expression and activity), while others—a reduction in DA levels in tissue and extracellular space and in VMAT2 and DAT expression—manifest the functional failure. In symptomatic mice, only a few parameters (spontaneous DA release and uptake, MAO-B gene expression and activity) remained at the same level as at presymptomatic stage, while most parameters (DA level in tissue and extracellular space, DA-stimulated release, VMAT2 and DAT contents), decreased, showing decompensation, which was enhanced by increasing MAO-A activity. Thus, this study provides a comprehensive assessment of the molecular mechanisms of neuroplasticity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine models of preclinical and clinical stages of PD, which could potentially serve as a powerful tool for translational medicine.

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Acknowledgements

We thank Dr. L. E. Eiden (Section on Molecular Neuroscience, Laboratory of Cellular and Molecular Regulation, NIMH, Bethesda, USA) for the kind gift of antibodies to VMAT2 and Professor N. F. Myasoedov (Institute of Molecular Genetics of the Russian Academy of Science, Moscow, Russia) for radiolabeling of DA.

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Author notes

  1. Eduard R. Mingazov and Gulnara R. Khakimova contributed equally to the work.

Authors and Affiliations

  1. Laboratory of Neural and Neuroendocrine Regulations, Institute of Developmental Biology RAS, 26, Vavilov St., Moscow, Russia, 119334

    Eduard R. Mingazov, Gulnara R. Khakimova, Elena A. Kozina & Michael V. Ugrumov

  2. Laboratory of Pharmacoproteomics, Institute of Biomedical Chemistry RAS, 10 Building 8, Pogodinskaya St, Moscow, Russia, 119121

    Alexei E. Medvedev & Olga A. Buneeva

  3. Laboratory of Neurochemical Mechanisms of Learning and Memory, Institute of Higher Nervous Activity and Neurophysiology RAS, 5A Butlerov St., Moscow, Russia, 117485

    Ara S. Bazyan

  4. Department of Psychology, Faculty of Social Sciences, The National Research University Higher School of Economics, 20 Myasnitskaya St., Moscow, Russia, 101000

    Michael V. Ugrumov

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  1. Eduard R. Mingazov
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  2. Gulnara R. Khakimova
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  3. Elena A. Kozina
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Correspondence to Michael V. Ugrumov.

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All the experimental procedures were carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23) revised 1996 and the UK Animals (Scientific Procedures) Act 1986 and associated guidelines or the European Communities Council Directive of 24 November 1986 (86/609/EEC) for care and use of laboratory animals and were approved by the Animal Care and Use Committee of the Institute of Developmental Biology of the Russian Academy of Sciences.

Funding

This study was supported by grant from the Federal Targeted Program Research and Development in Priority Areas of Scientific-Technological Complex of Russia for 2014–2020 years of the Ministry of Education and Science of RF (Grant: 14.604.21.0073).

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The authors declare that they have no competing interests.

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Mingazov, E.R., Khakimova, G.R., Kozina, E.A. et al. MPTP Mouse Model of Preclinical and Clinical Parkinson’s Disease as an Instrument for Translational Medicine. Mol Neurobiol 55, 2991–3006 (2018). https://doi.org/10.1007/s12035-017-0559-6

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