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

• Type of Material: Article
• Authors: C Sampath, Meharry Medical College; R Kalpana, Meharry Medical College; T Ansah, Meharry Medical College; C Charlton, Meharry Medical College; A Hale, University of Oxford; KM Channon, University of Oxford; Shanthi Srinivasan, Emory University; PR Gangula, Meharry Medical College
• Language: English
• Date: 2019-12-01
• Publisher: Springer (part of Springer Nature): Springer Open Choice Hybrid Journals - CC-BY-NC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019, Springer Science+Business Media, LLC, part of Springer Nature.
• Final Published Version (URL): http://dx.doi.org/10.1007/s10620-019-05693-5
• Title of Journal or Parent Work: Digestive Diseases and Sciences
• ISSN: 0163-2116
• Volume: 64
• Issue: 12
• Start Page: 3502
• End Page: 3517
• Grant/Funding Information: 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.
• Keywords: OXIDATIVE STRESS; ALZHEIMERS-DISEASE; alpha-Synuclein; Nrf2; Tyrosine hydroxylase; PATHWAY; Gastroenterology & Hepatology; Nitric oxide synthase; Gastrointestinal motility; EXPRESSION; Parkinson's disease; NITRIC-OXIDE SYNTHASE; TETRAHYDROBIOPTERIN; ALPHA-SYNUCLEIN; NEUROPROTECTION; Life Sciences & Biomedicine; Tetrahydrobiopterin; Antioxidants; TRANSCRIPTION FACTOR NRF2; NEURONS; Science & Technology
• Research Categories: Biology, Neuroscience; Biology, Genetics

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.