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Reversible Pharmacological Induction of Motor Symptoms in MPTP-Treated Mice at the Presymptomatic Stage of Parkinsonism: Potential Use for Early Diagnosis of Parkinson’s Disease

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Abstract

A crucial event in the pathogenesis of Parkinson’s disease is the death of dopaminergic neurons of the nigrostriatal system, which are responsible for the regulation of motor function. Motor symptoms first appear in patients 20–30 years after the onset of the neurodegeneration, when there has been a loss of an essential number of neurons and depletion of compensatory reserves of the brain, which explains the low efficiency of treatment. Therefore, the development of a technology for the diagnosing of Parkinson’s disease at the preclinical stage is of a high priority in neurology. In this study, we have developed at an experimental model a fundamentally novel for neurology approach for diagnosis of Parkinson’s disease at the preclinical stage. This methodology, widely used for the diagnosis of chronic diseases in the internal medicine, is based on the application of a challenge test that temporarily increases the latent failure of a specific functional system, thereby inducing the short-term appearance of clinical symptoms. The provocation test was developed by a systemic administration of α-methyl-p-tyrosine (αMpT), a reversible inhibitor of tyrosine hydroxylase to MPTP-treated mice at the presymptomatic stage of parkinsonism. For this, we first selected a minimum dose of αMpT, which caused a decrease of the dopamine level in the striatum of normal mice below the threshold at which motor dysfunctions appear. Then, we found the maximum dose of αMpT at which a loss of dopamine in the striatum of normal mice did not reach the threshold level, and motor behavior was not impaired. We showed that αMpT at this dose induced a decrease of the dopamine concentration in the striatum of MPTP-treated mice at the presymptomatic stage of parkinsonism below a threshold level that results in the impairment of motor behavior. Finally, we proved that αMpT exerts a temporal and reversible influence on the nigrostriatal dopaminergic system of MPTP-treated mice with no long-term side effects on other catecholaminergic systems. Thus, the above experimental data strongly suggest that αMpT-based challenge test might be considered as the provocation test for Parkinson’s disease diagnosis at the preclinical stage in the future clinical trials.

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Abbreviations

AADC:

Aromatic L-amino acid decarboxylase

DA:

Dopamine

HPLC-ED:

High-performance liquid chromatography with electrochemical detection

l-DOPA:

l-3,4-Dihydroxyphenylalanine

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NE:

Norepinephrine

SN:

Substantia nigra

αMpT:

α-methyl-p-tyrosine

ТН:

Tyrosine hydroxylase

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Acknowledgements

We thank Ekaterina Degtyareva and Anna Kolacheva for technical assistance.

Authors’ Contributions

G.R.K. performed the motor behavior experiments, HPLC and statistical analysis; E.A.K. performed immunohistochemistry and statistical analysis; V.G.K. assisted with motor behavior experiments; G.R.K., E.A.K. analyzed the data; M.V.U. initiated and coordinated the study; G.R.K., E.A.K., M.V.U. wrote the manuscript.

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    Authors and Affiliations

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

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

    2. Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathophysiology RAMS, 8 Baltiiskaya St, Moscow, 125315, Russia

      Valerian G. Kucheryanu

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

      Michael V. Ugrumov

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    1. Gulnara R. Khakimova
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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.

    Competing Interests

    The authors declare that they have no competing interests.

    Funding

    This work was supported by the Federal Targeted Programme Research and Development in Priority Areas of Scientific and Technological Complex of Russia for 2014–2020 years of the Ministry of Education and Science of RF (a contract No 14.604.21.0073 for 2014–2016).

    Additional information

    Gulnara R. Khakimova and Elena A. Kozina contributed equally to this work.

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    Khakimova, G.R., Kozina, E.A., Kucheryanu, V.G. et al. Reversible Pharmacological Induction of Motor Symptoms in MPTP-Treated Mice at the Presymptomatic Stage of Parkinsonism: Potential Use for Early Diagnosis of Parkinson’s Disease. Mol Neurobiol 54, 3618–3632 (2017). https://doi.org/10.1007/s12035-016-9936-9

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