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Increased Mmp/Reck Expression Ratio Is Associated with Increased Recognition Memory Performance in a Parkinson’s Disease Animal Model

  • Adauto Spindola
  • Adriano D. S. Targa
  • Lais Soares Rodrigues
  • Sheila Maria Brochado Winnischofer
  • Marcelo M. S. Lima
  • Mari Cleide Sogayar
  • Marina Trombetta-LimaEmail author
Article

Abstract

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide. Among its non-motor symptoms, sleep disorders are extremely common, being linked to cognitive and memory disruption. The microenvironment, particularly the extracellular matrix (ECM), is deeply involved in memory consolidation as well as in neuropathological processes, such as inflammation, damage to the blood-brain barrier and neuronal death. To better understand ECM dynamics in PD memory disturbances, we investigated the orchestrated expression of Mmps (Mmp-3, Mmp-7, and Mmp-9) and their modulators (Reck and Timp-3) in a rotenone-induced PD model. Also, we introduced an additional intervention in the memory process through rapid eye movement sleep deprivation (REMSD). We observed a REMSD-induced trend in reversing the memory impairment caused by rotenone administration. Associated to this phenotype, we observed a significant increase in Mmp-7/Reck and Mmp-9/Reck mRNA expression ratio in the substantia nigra and Mmp-9/Reck ratio in the hypothalamus. Moreover, the positive correlation of Mmp/Reck expression ratios between the substantia nigra and the striatum, observed upon rotenone infusion, was reversed by REMSD. Taken together, our results suggest a potential orchestrated association between an increase in Mmp-7 and Mmp-9/Reck expression ratios in the substantia nigra and a possible positive effect on cognitive performance in subjects affected by PD.

Keywords

Parkinson’s disease Sleep deprivation Reck gene Mmp-9 Mmp-7 Extracellular matrix dynamics Recognition memory 

Abbreviations

D1

Dopamine receptor 1

D2

Dopamine receptor 2

ECM

Extracellular matrix

GDNF

Glial cell–derived neurotrophic factor

Mmp

Matrix metalloproteinase

MPTP

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

NGF

Nerve growth factor

PD

Parkinson’s disease

Reck

reversion-inducing cysteine-rich protein with Kazal motifs

REM

rapid eye movement

REMSD

REM sleep deprivation

SNpc

substantia nigra pars compacta

Notes

Acknowledgments

The authors are grateful for the competent technical support offered by Marluce Mantovani, Zizi de Mendonça, Débora Cristina da Costa Lopes, Alan Pereira dos Santos, and Michely Reis. In memoriam of Débora Cristina da Costa Lopes, whose dedication and kindness are deeply missed.

Author Contributions

AS was responsible for conception and design of the study, main experimental work, data analysis, and drafting of the manuscript. ADST was involved in the study design, main animal experimental work, data analysis, and drafting of the manuscript. LSR was involved in the experimental work and drafting of the manuscript. SMBW, MMSL, and MCS were involved in conception and design of the study, drafting, and revision of the manuscript. MTL was responsible for the study conception and design, supervision of the experimental work, data analysis, drafting, and revision of the manuscript.

Funding Information

This work was supported by FAPESP (São Paulo State Research Foundation) (grant numbers 2016/05311-2 to MCS; MTL was a recipient of FAPESP fellowships numbers 2016/18277-7 and 2015/26328-8), BNDES (Brazilian National Bank for Economic and Social Development) (grant number 09.2.1066.1 to MCS), CAPES (Coordination for the Improvement of Higher Education Personnel) (PVE program, grant number 88881.068070/2014-01 to MCS), CNPq (National Council for Scientific and Technological Development) (grant numbers 431279/2016-0 to MMSL, 307066/2012-6, 479356/2010-6 to SMBW and 401430/2013-8, 457601/2013-2, 409960/2013-6, 426896/2016-5, and 465656/2014-5 to MCS, MMSL is a recipient of CNPq Productivity Award number 305986/2016-3), FINEP (Brazilian Federal Funding Agency for Studies and Projects) (grant numbers 01.06.0664.00 and 01.08.0622.00 to MCS), Araucaria Foundation (grant number 219/2010-17497 to SMBW), and Ministries of Science and Technology (MCTI) and of Health (MS-DECIT).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

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Supplementary Figure 1 (DOCX 286 kb)
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Supplementary Figure 3 (DOCX 293 kb)
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Supplementary Figure 4 (DOCX 830 kb)
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Supplementary Table 1 (DOCX 13 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Adauto Spindola
    • 1
  • Adriano D. S. Targa
    • 2
    • 3
  • Lais Soares Rodrigues
    • 2
    • 3
  • Sheila Maria Brochado Winnischofer
    • 4
    • 5
  • Marcelo M. S. Lima
    • 2
    • 3
  • Mari Cleide Sogayar
    • 1
    • 6
  • Marina Trombetta-Lima
    • 1
    Email author
  1. 1.Núcleo de Terapia Celular e Molecular (NUCEL), Faculdade de MedicinaUniversidade de São PauloSao PauloBrazil
  2. 2.Laboratório de Neurofisiologia, Departamento de FisiologiaUniversidade Federal do ParanáCuritibaBrazil
  3. 3.Departamento de FarmacologiaUniversidade Federal do ParanáCuritibaBrazil
  4. 4.Departamento de Bioquímica e Biologia MolecularUniversidade Federal do ParanáCuritibaBrazil
  5. 5.Departamento de Biologia Celular e MolecularUniversidade Federal do ParanáCuritibaBrazil
  6. 6.Departamento de Bioquímica, Instituto de QuímicaUniversidade de São PauloSao PauloBrazil

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