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      N-Acetyl Cysteine May Support Dopamine Neurons in Parkinson's Disease: Preliminary Clinical and Cell Line Data

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          Abstract

          Backgound

          The purpose of this study was to assess the biological and clinical effects of n-acetyl-cysteine (NAC) in Parkinson’s disease (PD).

          Methods

          The overarching goal of this pilot study was to generate additional data about potentially protective properties of NAC in PD, using an in vitro and in vivo approach. In preparation for the clinical study we performed a cell tissue culture study with human embryonic stem cell (hESC)-derived midbrain dopamine (mDA) neurons that were treated with rotenone as a model for PD. The primary outcome in the cell tissue cultures was the number of cells that survived the insult with the neurotoxin rotenone. In the clinical study, patients continued their standard of care and were randomized to receive either daily NAC or were a waitlist control. Patients were evaluated before and after 3 months of receiving the NAC with DaTscan to measure dopamine transporter (DAT) binding and the Unified Parkinson’s Disease Rating Scale (UPDRS) to measure clinical symptoms.

          Results

          The cell line study showed that NAC exposure resulted in significantly more mDA neurons surviving after exposure to rotenone compared to no NAC, consistent with the protective effects of NAC previously observed. The clinical study showed significantly increased DAT binding in the caudate and putamen (mean increase ranging from 4.4% to 7.8%; p<0.05 for all values) in the PD group treated with NAC, and no measurable changes in the control group. UPDRS scores were also significantly improved in the NAC group (mean improvement of 12.9%, p = 0.01).

          Conclusions

          The results of this preliminary study demonstrate for the first time a potential direct effect of NAC on the dopamine system in PD patients, and this observation may be associated with positive clinical effects. A large-scale clinical trial to test the therapeutic efficacy of NAC in this population and to better elucidate the mechanism of action is warranted.

          Trial Registration

          ClinicalTrials.gov NCT02445651

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          Most cited references49

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          Oxidative stress and the pathogenesis of Parkinson's disease.

          P Jenner, W Olanow (1996)
          Current concepts of the pathogenesis of Parkinson's disease (PD) center on the formation of reactive oxygen species and the onset of oxidative stress leading to oxidative damage to substantia nigra pars compacta. Extensive postmortem studies have provided evidence to support the involvement of oxidative stress in the pathogenesis of PD; in particular, these include alterations in brain iron content, impaired mitochondrial function, alterations in the antioxidant protective systems (most notably superoxide dismutase [SOD] and reduced glutathione [GSH]), and evidence of oxidative damage to lipids, proteins, and DNA. Iron can induce oxidative stress, and intranigral injections have been shown to induce a model of progressive parkinsonism. A loss of GSH is associated with incidental Lewy body disease and may represent the earliest biochemical marker of nigral cell loss. GSH depletion alone may not result in damage to nigral neurons but may increase susceptibility to subsequent toxic or free radical exposure. The nature of the free radical species responsible for cell death in PD remains unknown, but there is evidence of involvement of hydroxyl radical (OH.), peroxynitrite, and nitric oxide. Indeed, OH. and peroxynitrite formation may be critically dependent on nitric oxide formation. Central to many of the processes involved in oxidative stress and oxidative damage in PD are the actions of monoamine oxidase-B (MAO-B). MAO-B is essential for the activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to 1-methyl-4-phenylpyridinium ion, for a component of the enzymatic conversion of dopamine to hydrogen peroxide (H2O2), and for the activation of other potential toxins such as isoquinolines and beta-carbolines. Thus, the inhibition of MAO-B by drugs such as selegiline may protect against activation of some toxins and free radicals formed from the MAO-B oxidation of dopamine. In addition, selegiline may act through a mechanism unrelated to MAO-B to increase neurotrophic factor activity and upregulate molecules such as glutathione, SOD, catalase, and BCL-2 protein, which protect against oxidant stress and apoptosis. Consequently, selegiline may be advantageous in the long-term treatment of PD.
          Article 0 comments Cited 140 times – based on 0 reviews     Review now
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            Slower progression of Parkinson's disease with ropinirole versus levodopa: The REAL-PET study.

            D. Bradford Brooks, Ashley Watts, W Poewe … (2003)
            Preclinical studies suggest ropinirole (a D2/D3 dopamine agonist) may be neuroprotective in Parkinson's disease (PD), and a pilot clinical study using (18)F-dopa positron emission tomography (PET) suggested a slower loss of striatal dopamine storage with ropinirole compared with levodopa. This prospective, 2-year, randomized, double-blind, multinational study compared the rates of loss of dopamine-terminal function in de novo patients with clinical and (18)F-dopa PET evidence of early PD, randomized 1 to 1 to receive either ropinirole or levodopa. The primary outcome measure was reduction in putamen (18)F-dopa uptake (Ki) between baseline and 2-year PET. Of 186, 162 randomized patients were eligible for analysis. A blinded, central, region-of-interest analysis showed a significantly lower reduction (p = 0.022) in putamen Ki over 2 years with ropinirole (-13.4%; n = 68) compared with levodopa (-20.3%; n = 59; 95% confidence interval [CI], 0.65-13.06). Statistical parametric mapping localized lesser reductions in (18)F-dopa uptake in the putamen and substantia nigra with ropinirole. The greatest Ki decrease in each group was in the putamen (ropinirole, -14.1%; levodopa, -22.9%; 95% CI, 4.24-13.3), but the decrease was significantly lower with ropinirole compared with levodopa (p < 0.001). Ropinirole is associated with slower progression of PD than levodopa as assessed by (18)F-dopa PET.
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              Glutathione, oxidative stress and neurodegeneration.

              J Dichgans, J Seyfried, J. Schulz … (2000)
              There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species and mitochondrial dysfunction. Here, we review the evidence for a disturbance of glutathione homeostasis that may either lead to or result from oxidative stress in neurodegenerative disorders. Glutathione is an important intracellular antioxidant that protects against a variety of different antioxidant species. An important role for glutathione was proposed for the pathogenesis of Parkinson's disease, because a decrease in total glutathione concentrations in the substantia nigra has been observed in preclinical stages, at a time at which other biochemical changes are not yet detectable. Because glutathione does not cross the blood-brain barrier other treatment options to increase brain concentrations of glutathione including glutathione analogs, mimetics or precursors are discussed.
              Article 0 comments Cited 82 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Yun Wang: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 16 June 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 6
                Electronic Location Identifier: e0157602
                Affiliations
                [1 ]Myrna Brind Center of Integrative Medicine, Thomas Jefferson University, Philadelphia, PA, United States of America
                [2 ]Movement Disorders Center, Department of Neurology, Thomas Jefferson University, Philadelphia, PA, United States of America
                [3 ]Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA, United States of America
                [4 ]Division of Nuclear Medicine, Department of Radiology, Thomas Jefferson University, Philadelphia, PA, United States of America
                National Health Research Institutes, TAIWAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: DM GZ DK TWL NW AB CI LI AN. Performed the experiments: DM GZ DK TWL NW JC XW AB LZ BB CI LI AN. Analyzed the data: DM GZ DK TWL NW JC XW AB CI LI AN. Contributed reagents/materials/analysis tools: DM GZ DK TWL NW JC XW AB LZ BB CI LI AN. Wrote the paper: DM GZ DK TWL NW JC XW AB LZ BB CI LI AN.

                Article
                Publisher ID: PONE-D-16-07472
                DOI: 10.1371/journal.pone.0157602
                PMC ID: 4911055
                PubMed ID: 27309537
                SO-VID: 90a4f443-8d98-4e8d-8fc8-b0cc6edfa22f
                Copyright © © 2016 Monti et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 22 February 2016
                Date accepted : 31 May 2016
                Page count
                Figures: 3, Tables: 5, Pages: 15
                Funding
                Funded by: Marcus Foundation
                Award Recipient :
                The Marcus Foundation supported this research study. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Neurodegenerative Diseases
                Subject: Movement Disorders
                Subject: Parkinson Disease
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Neurons
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Cellular Neuroscience
                Subject: Neurons
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Chemical Compounds
                Subject: Organic Compounds
                Subject: Amines
                Subject: Catecholamines
                Subject: Dopamine
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Organic Chemistry
                Subject: Organic Compounds
                Subject: Amines
                Subject: Catecholamines
                Subject: Dopamine
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Neurochemistry
                Subject: Neurotransmitters
                Subject: Biogenic Amines
                Subject: Catecholamines
                Subject: Dopamine
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Neurochemistry
                Subject: Neurotransmitters
                Subject: Biogenic Amines
                Subject: Catecholamines
                Subject: Dopamine
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Hormones
                Subject: Catecholamines
                Subject: Dopamine
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Peptides
                Subject: Glutathione
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Oxidative Stress
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Brain
                Subject: Brainstem
                Subject: Midbrain
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Brain
                Subject: Brainstem
                Subject: Midbrain
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Dopamine Transporters
                Subject: Research and Analysis Methods
                Subject: Imaging Techniques
                Subject: Neuroimaging
                Subject: Single Photon Emission Computed Tomography
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Neuroimaging
                Subject: Single Photon Emission Computed Tomography
                Subject: Medicine and Health Sciences
                Subject: Diagnostic Medicine
                Subject: Diagnostic Radiology
                Subject: Tomography
                Subject: Single Photon Emission Computed Tomography
                Subject: Research and Analysis Methods
                Subject: Imaging Techniques
                Subject: Diagnostic Radiology
                Subject: Tomography
                Subject: Single Photon Emission Computed Tomography
                Subject: Medicine and Health Sciences
                Subject: Radiology and Imaging
                Subject: Diagnostic Radiology
                Subject: Tomography
                Subject: Single Photon Emission Computed Tomography
                Custom metadata
                Data Availability All relevant data are available in the paper and its Supporting Information files.

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