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N-acetylcysteine Boosts Brain and Blood Glutathione in Gaucher and Parkinson Diseases
Open accessAbstract
OBJECTIVE: This study aimed to determine if the antioxidant N-acetylcysteine (NAC) is able to alter peripheral and central redox capabilities in patients with Parkinson disease (PD) or Gaucher disease (GD). METHODS: The study included nondemented adult subjects: 3 with PD, 3 with GD, and 3 healthy controls. Baseline brain glutathione (GSH) concentrations were measured using 7-T magnetic resonance spectroscopy (MRS). Baseline blood reduced-to-oxidized GSH ratios were determined for each subject. Brain GSH concentrations and blood redox ratios were then determined during and at specified time points after a single, 150-mg/kg NAC infusion. RESULTS: N-acetylcysteine increased blood GSH redox ratios in those with PD and GD and healthy controls, which was followed by an increase in brain GSH concentrations in all subjects. CONCLUSIONS: This is the first demonstration that with MRS, it is possible to directly measure and monitor increases in brain GSH levels in the human brain in response to a single, intravenous administration of NAC. This work shows the potential utility of MRS monitoring, which could assist in determining dosing regimens for clinical trials of this potentially useful antioxidant therapy for PD disease, GD, and other neurodegenerative disorders.
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“In a trial with patients suffering from PD was glutathione (GSH) level quantitatively monitored by Magnetic Resonance Imaging (MRI) following intravenously administrated 150 mg/kg of NAC. In all studied subjects the level of GSH increased, however, returned back to its original level after 120 min (Holmay et al. 2013).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Holmay et al. 2013
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Citations
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Alpha synuclein post translational modifications: potential targets for Parkinson’s disease therapy?
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Delgobo, M., Agnes, J. P., Gonçalves, R. M., dos Santos, V. W., Parisotto, E. B., Zamoner, A., & Zanotto‐Filho, A. (2019) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2019.02.012 · Cited by 42
Jiang, X., Wu, K., Ye, X., Xie, T., Zhang, P., Blass, B. E., & Bai, R. (2023) · Medicinal Research Reviews · doi:10.1002/med.21939 · Cited by 40
N -Acetylcysteine for Nonsuicidal Self-Injurious Behavior in Adolescents: An Open-Label Pilot Study
Cullen, K. R., Klimes‐Dougan, B., Schreiner, M. W., Carstedt, P. A., Marka, N. A., Nelson, K. J., Miller, M. J., Reigstad, K. M., Westervelt, A., Gunlicks‐Stoessel, M., et al. (2017) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2017.0032 · Cited by 40
“Human research has shown that NAC crosses the blood-brain barrier (Katz et al. 2015) and acutely increases blood and brain GSH concentrations (Holmay et al. 2013).”
BackgroundBrancaccio, M., Mennitti, C., Cesaro, A., Fimiani, F., Moscarella, E., Caiazza, M., Gragnano, F., Ranieri, A., D’Alicandro, G., Tinto, N., et al. (2020) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph17249424 · Cited by 40
Mitochondria-Targeted Antioxidant Therapeutics for Traumatic Brain Injury
Modi, H. R., Musyaju, S., Ratcliffe, M., Shear, D. A., Scultetus, A. H., & Pandya, J. D. (2024) · Antioxidants · doi:10.3390/antiox13030303 · Cited by 44
“In keeping with this, NAC and its analogs, such as the cysteine supplement, are effective at raising levels of glutathione in various neurological diseases and injuries, preclinically and clinically [126–129].”
BackgroundReinforcing mitochondrial functions in aging brain: An insight into Parkinson's disease therapeutics
Chandra, G., Shenoi, R. A., Anand, R., Rajamma, U., & Mohanakumar, K. P. (2017) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2017.12.004 · Cited by 39
N-Acetyl-l-Cysteine Protects Astrocytes against Proteotoxicity without Recourse to Glutathione
Gleixner, A. M., Hutchison, D. F., Sannino, S., Bhatia, T. N., Leak, L. C., Flaherty, P. T., Wipf, P., Brodsky, J. L., & Leak, R. K. (2017) · Molecular Pharmacology · doi:10.1124/mol.117.109926 · Cited by 36
“motor deficits and dopamine transporter binding in this condition (Holmay et al., 2013; Katz et al., 2015; Martinez-Banaclocha, 2012; Monti et al., 2016; Reyes et al., 2016).”
Lee, C., Su, C.-H., Tsai, P., Yang, M., Ho, Y., Lee, S., Chen, C., Chen, W., Lin, M., Chen, C., et al. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.09.054 · Cited by 37
Leathem, A., Ortíz, T., Dennis, J. M., & Witting, P. K. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23136923 · Cited by 36
“Similarly, intravenous infusion of NAC increases both brain GSH concentration and blood glutathione redox ratio in PD patients as well as healthy controls, although this effect is, as expected, more pronounced in the PD patient group [82].”
BackgroundMarkoutsa, E., & Xu, P. (2017) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.6b01028 · Cited by 36
Magnetic resonance imaging as a potential biomarker for Parkinson's disease
Tuite, P. (2015) · Translational research · doi:10.1016/j.trsl.2015.12.006 · Cited by 36
“dose of NAC increased blood Gln redox levels by 200%–1000%, which were followed by 30% increases in brain Gln concentrations (Fig 1).(146) To follow up on this work and to move to a more practical repeated oral NAC dose regimen for patient studies, we conducted a 4 week oral NAC dose study in PD and control subjects a…”
BackgroundMethodSelf-citationThe use of magnetic resonance spectroscopy for assessing the effect of diet on cognition
Scavuzzo, C. J., Moulton, C. J., & Larsen, R. J. (2016) · Nutritional Neuroscience · doi:10.1080/1028415x.2016.1218191 · Cited by 35
New Therapeutics to Modulate Mitochondrial Function in Neurodegenerative Disorders
Wilkins, H., & Morris, J. K. (2017) · Current Pharmaceutical Design · doi:10.2174/1381612822666161230144517 · Cited by 34
Brain Magnetic Resonance Imaging (MRI) as a Potential Biomarker for Parkinson’s Disease (PD)
Tuite, P. (2017) · Brain Sciences · doi:10.3390/brainsci7060068 · Cited by 34
“NAC study showed initial blood (200%–1000%) and then brain (~30%) increases in GSH concentrations [116].”
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“In addition, one MRS study suggested that there was an increase in brain glutathione levels in patients receiving an intravenous but not oral dose of NAC (13).”
BackgroundInfluentialPoletti, S., Paolini, M., Mazza, M. G., Palladini, M., Furlan, R., Rovere, P. Q., & Benedetti, F. (2022) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2022.06.008 · Cited by 34
Deelchand, D. K., Marjańska, M., Hodges, J. S., & Terpstra, M. (2016) · NMR in Biomedicine · doi:10.1002/nbm.3507 · Cited by 33
Self-citationLower Posterior Cingulate Cortex Glutathione Levels in Obsessive-Compulsive Disorder
Brennan, B. P., Jensen, J. E., Perriello, C., Pope, H. G., Jenike, M. A., Hudson, J. I., Rauch, S. L., & Kaufman, M. J. (2015) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2015.12.003 · Cited by 34
“One (73) found no change in individuals with depression following a sixweek course of treatment with the SSRI escitalopram and the other (80) demonstrated an acute GSH increase following intravenous NAC administration in individuals with Gaucher and Parkinson’s diseases.”
BackgroundOxidative damage and redox in Lysosomal Storage Disorders: Biochemical markers
Donida, B., Jacques, C. E. D., Mescka, C. P., Rodrigues, D. G. B., Marchetti, D. P., Ribas, G. S., Giugliani, R., & Vargas, C. R. (2017) · Clinica Chimica Acta · doi:10.1016/j.cca.2017.01.007 · Cited by 33
Yi, L., Tan, E. K., & Zhou, Z. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25094643 · Cited by 33
“A multi-drug combination therapy including TH inhibitors should be further explored in clinical trials in PD patients.”
BackgroundGoldstein, D. S., Jinsmaa, Y., Sullivan, P., & Sharabi, Y. (2017) · Neurochemical Research · doi:10.1007/s11064-017-2371-0 · Cited by 31
“NAC has acceptable bioavailability [22, 23], and in humans NAC increases brain glutathione content [24].”
BackgroundLowe, D. W., Fraser, J. L., Rollins, L. G., Bentzley, J. P., Nie, X., Martin, R. H., Singh, I., & Jenkins, D. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.06.004 · Cited by 28
“NAC rapidly crosses the blood brain barrier and mitigates oxidative stress by directly scavenging oxygen free radicals and supplying cysteine, the ratelimiting substrate in synthesis of glutathione, a m jor intracellular antioxidant [8, 9].”
Benvenutti, R., Marcon, M., Reis, C. G., Nery, L. R., Miguel, C., Herrmann, A. P., Vianna, M. R. M. R., & Piato, Â. (2018) · PeerJ · doi:10.7717/peerj.4957 · Cited by 28
Segura‐Aguilar, J., & Mannervik, B. (2023) · Antioxidants · doi:10.3390/antiox12030673 · Cited by 27
“to increase the GSH concentration in the brain [8,90].”
BackgroundN-Acetyl cysteine prevents synergistic, severe toxicity from two hits of oxidative stress
Unnithan, A. S., Jiang, Y., Rumble, J. L., Pulugulla, S. H., Posimo, J. M., Gleixner, A. M., & Leak, R. K. (2013) · Neuroscience Letters · doi:10.1016/j.neulet.2013.12.023 · Cited by 27
Zhang, Y., Cui, W., Zhai, Q., Zhang, T., & Wen, X. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2017.6787 · Cited by 27
“NAC has been reported to cross the blood brain barrier (10,11), decrease oxidative stress and inflammatory cytokine production, replenish GSH levels, and thus ameliorate autism-associated irritability, including self-injurious behavior (12).”
Vieira, G. D. L. T., Lossie, A. C., Lay, D. C., Jr., Radcliffe, J. S., & Garner, J. P. (2017) · PLoS ONE · doi:10.1371/journal.pone.0175222 · Cited by 26
Girgis, R. R., Baker, S. C., Mao, X., Gil, R. B., Javitt, D. C., Kantrowitz, J. T., Gu, M., Spielman, D. M., Ojeil, N., Xu, X., et al. (2019) · Psychiatry Research · doi:10.1016/j.psychres.2019.03.018 · Cited by 26
“However, a study in Parkinson and Gaucher diseases reported GSH elevations in response to a single intravenous dose of NAC (Holmay et al., 2013), likely due to the generally higher bioavailability of intravenously administered NAC.”
BackgroundMethodVirel, A., Dudka, I., Laterveer, R., & af Bjerkén, S. (2019) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2019.06.003 · Cited by 25
Inflammation, Obsessive-Compulsive Disorder, and Related Disorders
Meyer, J. H. (2021) · Current topics in behavioral neurosciences · doi:10.1007/7854_2020_210 · Cited by 26
The Multiple Sclerosis Modulatory Potential of Natural Multi-Targeting Antioxidants
Theodosis‐Nobelos, P., & Rekka, E. A. (2022) · Molecules · doi:10.3390/molecules27238402 · Cited by 27
“N-acetylcysteine (NAC) is a very well-established antioxidant, GSH precursor, increasing GSH in brain [112].”
Background
Metadata
- Authors
- Holmay, M. J., Terpstra, M., Coles, L. D., Mishra, U., Ahlskog, M., Öz, G., Cloyd, J. C., & Tuite, P. J.
- Affiliations
- University of Minnesota (US)
- Cornell University (US)
- Corresponding author
- Holmay, Mary J.
- ORCID
- Venue
- Clinical Neuropharmacology
- Published
- 2013-07
- Volume
- 36
- Issue
- 4
- Pages
- 103-106
- ISSN
- 0362-5664 (ISSN-L)
- PMC
- PMC3934795
- OpenAlex
- W2010686114
- Cited by
- 216
- References
- 29
- Citations by year
- 2026: 14 · 2025: 14 · 2024: 14 · 2023: 19 · 2022: 20 · 2021: 20 · 2020: 18 · 2019: 12 · 2018: 14 · 2017: 26 · 2016: 15 · 2015: 15 · 2014: 10 · 2013: 2
- FWCI
- 8.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (U54NS065768, P30NS076408)
- National Institute of Biomedical Imaging and Bioengineering (P41EB015894)
- National Center for Research Resources (S10RR026783, P41RR008079)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Keywords
- N-acetylcysteine, glutathione, Parkinson's disease, Gaucher disease, brain glutathione, antioxidant therapy, redox state, neurodegenerative diseases
- MeSH terms
- Acetylcysteine, Adolescent, Antioxidants, Antiparkinson Agents, Brain, Female, Gaucher Disease, Glutathione, Humans, Infusions, Intravenous, Kinetics, Magnetic Resonance Imaging, Male, Middle Aged, Neurons, Oxidation-Reduction, Parkinson Disease, Up-Regulation
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