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Bidirectional Neural Interaction Between Central Dopaminergic and Gut Lesions in Parkinson’s Disease Models

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Abstract

The exact mechanism of gut dysfunction in Parkinson’s disease and, conversely, the role of gut pathology in brain dopaminergic degeneration are controversial. We investigated the effects of nigral lesions on the colonic neurotransmission, the effect of gut inflammation on the nigrostriatal dopaminergic function, and the possible involvement of the vagus nerve and the local renin-angiotensin system (RAS). Nigrostriatal dopamine depletion was performed by bilateral injection 6-hydroxydopamine, and gut inflammation was induced by dextran sulfate sodium salt treatment in rats and mice, respectively, with or without vagal disruption. A decrease in central dopamine levels induced a decrease in colonic dopamine types 1 and 2 receptor expression together with an increase in the colonic levels of dopamine and a decrease in the levels of acetylcholine, which may explain a decrease in gut motility. Central dopaminergic depletion also induced an increase in the colonic levels of inflammatory and oxidative stress markers together with activation of the pro-inflammatory arm of the local RAS. Mice with acute (1 week) or subchronic (3 weeks) gut inflammation did not show a significant increase in colonic α-synuclein and phosphorylated α-synuclein expression during this relatively short survival period. Interestingly, we observed early changes in the nigrostriatal dopaminergic homeostasis, dopaminergic neuron death, and increased levels of nigral pro-inflammatory markers and RAS pro-inflammatory activity. The present results show that a dysregulation of the neural bidirectional gut-brain interaction may explain the early gut disturbances observed in parkinsonian patients, and also the increase in vulnerability of nigral dopaminergic neurons after gut inflammation.

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Abbreviations

6-OHDA:

6-Hydroxydopamine

Ach:

Acetylcholine

AngII:

Angiotensin II

AT1:

Angiotensin type 1 receptor

β-ACT:

β-Actin

BBB:

Blood-brain-barrier

CNS:

Central nervous system

D1:

Dopamine type 1

DAI:

Disease activity index

DMV:

Dorsal vagal motor nucleus

DOPAC:

3,4-Dihydroxyphenylacetic acid

DSS:

Sulfate sodium salt

ENS:

Enteric nervous system

GADPH:

Glyceraldehyde 3-phosphate dehydrogenase

GI:

Gastrointestinal

HPLC:

High-performance liquid chromatography

HVA:

Homovanillic acid

IL:

Interleukin

RAS:

Renin-angiotensin system

SN:

Substantia nigra

TH:

Tyrosine hydroxylase

WB:

Western blot

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Acknowledgements

We thank Pilar Aldrey, Iria Novoa, and Cristina Gianzo for their technical assistance.

Funding

This study is financially supported by Spanish Ministry of Economy and Competitiveness (BFU2015-70523), Spanish Ministry of Health (RD12/0019/0020, RD16/0011/0016 and CIBERNED), Galician Government (XUGA, Conselleria de Educacion; GRC2014/002), and FEDER (Regional European Development Fund).

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Authors and Affiliations

  1. Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, CIMUS, Faculty of Medicine, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain

    Pablo Garrido-Gil, Ana I. Rodriguez-Perez, Antonio Dominguez-Meijide, Maria J. Guerra & Jose L. Labandeira-Garcia

  2. Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain

    Pablo Garrido-Gil, Ana I. Rodriguez-Perez, Antonio Dominguez-Meijide, Maria J. Guerra & Jose L. Labandeira-Garcia

Authors
  1. Pablo Garrido-Gil
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  2. Ana I. Rodriguez-Perez
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  3. Antonio Dominguez-Meijide
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  4. Maria J. Guerra
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  5. Jose L. Labandeira-Garcia
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Contributions

JLL-G and PG-G conceived and supervised the whole study and wrote the manuscript; PG-G performed the experimental models and lesions; AD-M and PG-G performed HPLC analysis; and AR-P and MJG performed WB and PCR analyses. All authors edited the manuscript.

Corresponding author

Correspondence to Jose L. Labandeira-Garcia.

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The authors declare that they have no conflict of interest.

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Research Involving Animals

All procedures performed in studies involving animals were in accordance with with the European Directive 2010/63/EU and the Spanish RD/53/2013 for the protection of animals used for scientific purposes and were approved by the corresponding committee of the University of Santiago de Compostela (Spain) and the Galician Government (XUGA).

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Garrido-Gil, P., Rodriguez-Perez, A.I., Dominguez-Meijide, A. et al. Bidirectional Neural Interaction Between Central Dopaminergic and Gut Lesions in Parkinson’s Disease Models. Mol Neurobiol 55, 7297–7316 (2018). https://doi.org/10.1007/s12035-018-0937-8

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  • DOI: https://doi.org/10.1007/s12035-018-0937-8

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