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

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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.

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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.

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Authors and Affiliations

  1. Department of ODS and Research, School of Dentistry, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Blvd, Nashville, TN, 37208, USA

    C. Sampath, R. Kalpana & P. R. Gangula

  2. Department of Cancer Biology Physiology Pharmacology and Neuroscience, School of Medicine, Meharry Medical College, Nashville, TN, USA

    T. Ansah & C. Charlton

  3. Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK

    A. Hale

  4. Oxford Heart Centre, John Radcliffe Hospital, University of Oxford, Oxford, UK

    K. M. Channon

  5. Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, GA, USA

    S. Srinivasan

  6. Atlanta VA Health Care System, Decatur, Atlanta, GA, USA

    S. Srinivasan

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  1. C. Sampath
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  2. R. Kalpana
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Contributions

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.

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Correspondence to P. R. Gangula.

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Sampath, C., Kalpana, R., Ansah, T. et al. Impairment of Nrf2- and Nitrergic-Mediated Gastrointestinal Motility in an MPTP Mouse Model of Parkinson’s Disease. Dig Dis Sci 64, 3502–3517 (2019). https://doi.org/10.1007/s10620-019-05693-5

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