Flavonoids Protect Neuronal Cells from Oxidative Stress by Three Distinct Mechanisms
Abstract
Flavonoids are a family of antioxidants found in fruits and vegetables as well as in popular beverages such as red wine and tea. Although the physiological benefits of flavonoids have been largely attributed to their antioxidant properties in plasma, flavonoids may also protect cells from various insults. Nerve cell death from oxidative stress has been implicated in a variety of pathologies, including stroke, trauma, and diseases such as Alzheimer's and Parkinson's. To determine the potential protective mechanisms of flavonoids in cell death, the mouse hippocampal cell line HT-22, a model system for oxidative stress, was used. In this system, exogenous glutamate inhibits cystine uptake and depletes intracellular glutathione (GSH), leading to the accumulation of reactive oxygen species (ROS) and an increase in Ca(2+) influx, which ultimately causes neuronal death. Many, but not all, flavonoids protect HT-22 cells and rat primary neurons from glutamate toxicity as well as from five other oxidative injuries. Three structural requirements of flavonoids for protection from glutamate are the hydroxylated C3, an unsaturated C ring, and hydrophobicity. We also found three distinct mechanisms of protection. These include increasing intracellular GSH, directly lowering levels of ROS, and preventing the influx of Ca(2+) despite high levels of ROS. These data show that the mechanism of protection from oxidative insults by flavonoids is highly specific for each compound.
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Quercetin increases expression of SOD and GSH.
“to increase the expression of SOD and GSH (Ishige et al., 2001)”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as Ishige et al., 2001
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- Authors
- Ishige, K., Schubert, D., & Sagara, Y.
- Affiliations
- Salk Institute for Biological Studies (US)
- University of California San Diego (US)
- Corresponding author
- Schubert, David
- ORCID
- Schubert, David
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2001-02
- Volume
- 30
- Issue
- 4
- Pages
- 433-446
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W2133971230
- Cited by
- 841
- References
- 71
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 23 · 2023: 30 · 2022: 19 · 2021: 43 · 2020: 29 · 2019: 35 · 2018: 29 · 2017: 42 · 2016: 29 · 2015: 40 · 2014: 53 · 2013: 43 · 2012: 54
- FWCI
- 18.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Nihon University
- National Institutes of Health
- National Institute on Aging (AG05131, P50AG005131)
- Topics
- Health Sciences › Medicine › Biochemistry › Phytochemicals and Antioxidant Activities
- Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- flavonoids, oxidative stress, neuroprotection, glutamate excitotoxicity, glutathione depletion, reactive oxygen species, calcium influx, HT22 cells, hippocampal neurons, antioxidant defense, structure-activity relationship, neurodegenerative diseases
- MeSH terms
- Animals, Antioxidants, Calcium, Cell Line, Flavonoids, Free Radicals, Glutathione, Hippocampus, Neurons, Vitamin E, Cell Death, Reactive Oxygen Species, Oxidative Stress, Glutamic Acid, Mice
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