Repeated‐Dose Oral N‐Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress
Open accessAbstract
Parkinson's disease (PD) is associated with oxidative stress and decreased nigral glutathione (GSH), suggesting that therapies that boost GSH may have a disease‐modifying effect. Intravenous administration of a high dose of N‐acetylcysteine (NAC), a well‐known antioxidant and GSH precursor, increases blood and brain GSH in individuals with PD and with Gaucher disease and in healthy controls. To characterize the pharmacokinetics of repeated high oral doses of NAC and their effect on brain and blood oxidative stress measures, we conducted a 4‐week open‐label prospective study of oral NAC in individuals with PD (n = 5) and in healthy controls (n = 3). Brain GSH was measured in the occipital cortex using 1 H‐MRS at 3 and 7 tesla before and after 28 days of 6000 mg NAC/day. Blood was collected prior to dosing and at predetermined collection times before and after the last dose to assess NAC, cysteine, GSH, catalase, malondialdehyde (MDA) and 4‐hydroxynonenal (4‐HNE) concentrations and the reduced‐to‐oxidized GSH ratio (GSH/ glutathione disulfide [GSSG]). Symptomatic adverse events were reported by 3 of the 5 subjects with PD. NAC plasma concentration–time profiles were described by a first‐order absorption, 1‐compartment pharmacokinetic model. Although peripheral antioxidant measures (catalase and GSH/GSSG) increased significantly relative to baseline, indicators of oxidative damage, that is, measures of lipid peroxidation (4‐HNE and MDA) were unchanged. There were no significant increases in brain GSH, which may be related to low oral NAC bioavailability and small fractional GSH/GSSG blood responses. Additional studies are needed to further characterize side effects and explore the differential effects of NAC on measures of antioxidant defense and oxidative damage.
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Individuals taking 3000 mg of NAC every day for four weeks showed increased GSH/GSSG, but biomarkers of oxidative damage (lipid peroxidation) remained unchanged.
“Individuals were taking 3000 mg of NAC every day for four weeks. The results have shown that the level of GSH/GSSG increased, however, the biomarkers of oxidative damage (peroxidation of lipids) remained unchanged (Coles et al. 2018).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Coles et al. 2018
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- Authors
- Coles, L. D., Tuite, P. J., Öz, G., Mishra, U. R., Kartha, R. V., Sullivan, K. M., Cloyd, J. C., & Terpstra, M.
- Affiliations
- University of Minnesota (US)
- Corresponding author
- Coles, Lisa D.
- ORCID
- Venue
- The Journal of Clinical Pharmacology
- Publisher
- Wiley
- Published
- 2017-09-22
- Volume
- 58
- Issue
- 2
- Pages
- 158-167
- ISSN
- 0021-9754 (ISSN-L)
- 0091-2700
- 1552-4604
- PMC
- PMC5762253
- OpenAlex
- W2760325968
- Cited by
- 170
- References
- 42
- Citations by year
- 2026: 12 · 2025: 24 · 2024: 17 · 2023: 25 · 2022: 23 · 2021: 17 · 2020: 25 · 2019: 13 · 2018: 12 · 2017: 1
- FWCI
- 9.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Clinical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Parkinson's UK (K‐1401)
- National Institutes of Health (R01AG039396, UL1TR000114)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- N-acetylcysteine, Parkinson's disease, glutathione, oxidative stress, pharmacokinetics, oral administration, brain glutathione, lipid peroxidation, malondialdehyde, 4-hydroxynonenal, catalase, GSH/GSSG ratio, antioxidant defense, bioavailability, 1H magnetic resonance spectroscopy
- MeSH terms
- Acetylcysteine, Administration, Oral, Aged, Aged, 80 and over, Antioxidants, Brain, Catalase, Female, Glutathione, Humans, Male, Middle Aged, Models, Biological, Parkinson Disease, Oxidative Stress
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