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Impairment of Nrf2- and Nitrergic-Mediated Gastrointestinal Motility in an MPTP Mouse Model of Parkinson’s Disease

  • C. Sampath
  • R. Kalpana
  • T. Ansah
  • C. Charlton
  • A. Hale
  • K. M. Channon
  • S. Srinivasan
  • P. R. GangulaEmail author
Original Article

Abstract

Background

Gastrointestinal (GI) motility dysfunction is the most common non-motor symptom of Parkinson’s disease (PD). Studies have indicated that GI motility functions are impaired before the onset of PD.

Aims

To investigate the underlying mechanism of PD-induced GI dysmotility in MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine)-induced animal model.

Methods

C57BL/6 mice were administered with or without a selective dopamine neurotoxin, MPTP, to induce parkinsonian symptoms. In addition to in vivo studies, in vitro experiments were also conducted in colon specimens using l-methyl-4-phenylpyridinium (MPP+), a metabolic product of MPTP. Gastric emptying, colon motility, nitrergic relaxation, and western blot experiments were performed as reported.

Results

MPTP-induced PD mice showed decreased expression of nuclear factor erythroid 2-related factor (Nrf2) and its target phase II genes in gastric and colon neuromuscular tissues. Decreased levels of tetrahydrobiopterin (BH4, a critical cofactor for nNOS dimerization) associated with uncoupling of nNOS in gastric and colon tissues exposed to MPTP. Impaired enteric nitrergic system led to delayed gastric emptying and slower colonic motility compared to the control mice. In vitro results in colon specimens confirm that activation of Nrf2 restored MPP+-induced suppression of alpha-synuclein, tyrosine hydroxylase (TH), Nrf2, and heme oxygenase-1. In vitro exposure to L-NAME [N(w)-nitro-l-arginine methyl ester], a NOS synthase inhibitor, reduced protein expression of TH in colon tissue homogenates.

Conclusions

Loss of Nrf2/BH4/nNOS expression in PD impairs antioxidant gene expression, which deregulates NO synthesis, thereby contributing to the development of GI dysmotility and constipation. Nitric oxide appears to be important to maintain dopamine synthesis in the colon.

Keywords

Gastrointestinal motility Parkinson’s disease Nrf2 Antioxidants Tetrahydrobiopterin Nitric oxide synthase Tyrosine hydroxylase α-Synuclein 

Notes

Acknowledgment

The National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) under Award Number SC1GM121282 supported research reported in this publication. Finally, we thank the Meharry Office for Scientific Editing and Publications for editorial support.

Author’s contribution

P.G. contributed to conceptualization, methodology, and supervision; P. G. and K. R. were involved in data curation; C.S. and P. G. were involved in writing—original draft preparation; P. G., A. T., S. S., C. C., and C. K. M. were involved in writing—review and editing.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

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

Authors and Affiliations

  • C. Sampath
    • 1
  • R. Kalpana
    • 1
  • T. Ansah
    • 2
  • C. Charlton
    • 2
  • A. Hale
    • 3
  • K. M. Channon
    • 4
  • S. Srinivasan
    • 5
    • 6
  • P. R. Gangula
    • 1
    Email author
  1. 1.Department of ODS and Research, School of DentistryMeharry Medical CollegeNashvilleUSA
  2. 2.Department of Cancer Biology Physiology Pharmacology and Neuroscience, School of MedicineMeharry Medical CollegeNashvilleUSA
  3. 3.Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe HospitalUniversity of OxfordOxfordUK
  4. 4.Oxford Heart Centre, John Radcliffe HospitalUniversity of OxfordOxfordUK
  5. 5.Division of Digestive Diseases, Department of MedicineEmory UniversityAtlantaUSA
  6. 6.Atlanta VA Health Care SystemDecatur, AtlantaUSA

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