The antioxidants α‐lipoic acid and N ‐acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice
Abstract
Oxidative stress may play a crucial role in age-related neurodegenerative disorders. Here, we examined the ability of two antioxidants, alpha-lipoic acid (LA) and N-acetylcysteine (NAC), to reverse the cognitive deficits found in the SAMP8 mouse. By 12 months of age, this strain develops elevated levels of Abeta and severe deficits in learning and memory. We found that 12-month-old SAMP8 mice, in comparison with 4-month-old mice, had increased levels of protein carbonyls (an index of protein oxidation), increased TBARS (an index of lipid peroxidation) and a decrease in the weakly immobilized/strongly immobilized (W/S) ratio of the protein-specific spin label MAL-6 (an index of oxidation-induced conformational changes in synaptosomal membrane proteins). Chronic administration of either LA or NAC improved cognition of 12-month-old SAMP8 mice in both the T-maze footshock avoidance paradigm and the lever press appetitive task without inducing non-specific effects on motor activity, motivation to avoid shock, or body weight. These effects probably occurred directly within the brain, as NAC crossed the blood-brain barrier and accumulated in the brain. Furthermore, treatment of 12-month-old SAMP8 mice with LA reversed all three indexes of oxidative stress. These results support the hypothesis that oxidative stress can lead to cognitive dysfunction and provide evidence for a therapeutic role for antioxidants.
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Alpha-lipoic acid is a cofactor for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, which are key components in glucose metabolism; when given to dogs and rodents, it decreases oxidative damage in the brain and improves cognition.
“Alpha-lipoic acid is a cofactor for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, which are key components in glucose metabolism; when given to dogs and rodents, it decreases oxidative damage in the brain and improves cognition [149,150].”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [150]
NAC enters the brain at a very modest rate due to low bioavailability and membrane permeability.
“However, the beneficial effect of NAC has to be taken with caution since the current data is based on only a few studies showing relatively moderate clinical improvement in chronic schizophrenia patients, probably due to the low bioavailability and membrane permeability of NAC which enters the brain at a very modest rate (Farr et al., 2003).”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as Farr et al., 2003
Sulforaphane has shown some promise in a preliminary open-label trial for schizophrenia.
“one, sulforaphane, has shown some promise in a preliminary open-label trial for SZ 106”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as [106]
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“Alpha-lipoic acid is a cofactor for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, which are key components in glucose metabolism; when given to dogs and rodents, it decreases oxidative damage in the brain and improves cognition [149,150].”
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- Authors
- Farr, S. A., Poon, H. F., Dogrukol‐Ak, D., Drake, J., Banks, W. A., Eyerman, E., Butterfield, D. A., & Morley, J. E.
- Affiliations
- St. Louis VA Medical Center (US)
- University of Kentucky (US)
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2003-02-18
- Volume
- 84
- Issue
- 5
- Pages
- 1173-1183
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2132870100
- Cited by
- 459
- References
- 91
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 16 · 2023: 15 · 2022: 17 · 2021: 19 · 2020: 25 · 2019: 17 · 2018: 18 · 2017: 24 · 2016: 14 · 2015: 15 · 2014: 27 · 2013: 24 · 2012: 23
- FWCI
- 13.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Institute on Alcohol Abuse and Alcoholism (R01AA12743, R01AA012743)
- National Institute of Neurological Disorders and Stroke (R0-1 NS41863, R01NS041863)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Antioxidants, Aging, Portulaca oleracea
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- alpha-lipoic acid, N-acetylcysteine, antioxidants, oxidative stress, memory impairment, SAMP8 mice, aging, cognitive impairment, amyloid-beta, protein carbonyls, lipid peroxidation, blood-brain barrier, neurodegeneration
- MeSH terms
- Acetylcysteine, Age Factors, Animals, Antioxidants, Appetitive Behavior, Behavior, Animal, Blood-Brain Barrier, Brain, Cognition, Disease Models, Animal, Thioctic Acid, Male, Memory Disorders, Mice, Inbred Strains, Mice, Neurologic Mutants, Specific Pathogen-Free Organisms, Amyloid beta-Peptides, Treatment Outcome, Oxidative Stress, Maze Learning, Mice
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