Mechanisms of Neuroprotection by Quercetin: Counteracting Oxidative Stress and More

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Abstract

Increasing interest has recently focused on determining whether several natural compounds, collectively referred to as nutraceuticals, may exert neuroprotective actions in the developing, adult, and aging nervous system. Quercetin, a polyphenol widely present in nature, has received the most attention in this regard. Several studies in vitro, in experimental animals and in humans, have provided supportive evidence for neuroprotective effects of quercetin, either against neurotoxic chemicals or in various models of neuronal injury and neurodegenerative diseases. The exact mechanisms of such protective effects remain elusive, though many hypotheses have been formulated. In addition to a possible direct antioxidant effect, quercetin may also act by stimulating cellular defenses against oxidative stress. Two such pathways include the induction of Nrf2-ARE and induction of the antioxidant/anti-inflammatory enzyme paraoxonase 2 (PON2). In addition, quercetin has been shown to activate sirtuins (SIRT1), to induce autophagy, and to act as a phytoestrogen, all mechanisms by which quercetin may provide its neuroprotection.

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Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders.

Vittorio Calabrese, Carolin Cornelius, Albena T. Dinkova-Kostova … (2010)

Despite the capacity of chaperones and other homeostatic components to restore folding equilibrium, cells appear poorly adapted for chronic oxidative stress that increases in cancer and in metabolic and neurodegenerative diseases. Modulation of endogenous cellular defense mechanisms represents an innovative approach to therapeutic intervention in diseases causing chronic tissue damage, such as in neurodegeneration. This article introduces the concept of hormesis and its applications to the field of neuroprotection. It is argued that the hormetic dose response provides the central underpinning of neuroprotective responses, providing a framework for explaining the common quantitative features of their dose-response relationships, their mechanistic foundations, and their relationship to the concept of biological plasticity, as well as providing a key insight for improving the accuracy of the therapeutic dose of pharmaceutical agents within the highly heterogeneous human population. This article describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways, including sirtuin and Nrf2 and related pathways that integrate adaptive stress responses in the prevention of neurodegenerative diseases. Particular attention is given to the emerging role of nitric oxide, carbon monoxide, and hydrogen sulfide gases in hormetic-based neuroprotection and their relationship to membrane radical dynamics and mitochondrial redox signaling.

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Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies.

Claudine Manach, C Rémésy, Gary Williamson … (2004)

Polyphenols are abundant micronutrients in our diet, and evidence for their role in the prevention of degenerative diseases is emerging. Bioavailability differs greatly from one polyphenol to another, so that the most abundant polyphenols in our diet are not necessarily those leading to the highest concentrations of active metabolites in target tissues. Mean values for the maximal plasma concentration, the time to reach the maximal plasma concentration, the area under the plasma concentration-time curve, the elimination half-life, and the relative urinary excretion were calculated for 18 major polyphenols. We used data from 97 studies that investigated the kinetics and extent of polyphenol absorption among adults, after ingestion of a single dose of polyphenol provided as pure compound, plant extract, or whole food/beverage. The metabolites present in blood, resulting from digestive and hepatic activity, usually differ from the native compounds. The nature of the known metabolites is described when data are available. The plasma concentrations of total metabolites ranged from 0 to 4 mumol/L with an intake of 50 mg aglycone equivalents, and the relative urinary excretion ranged from 0.3% to 43% of the ingested dose, depending on the polyphenol. Gallic acid and isoflavones are the most well-absorbed polyphenols, followed by catechins, flavanones, and quercetin glucosides, but with different kinetics. The least well-absorbed polyphenols are the proanthocyanidins, the galloylated tea catechins, and the anthocyanins. Data are still too limited for assessment of hydroxycinnamic acids and other polyphenols. These data may be useful for the design and interpretation of intervention studies investigating the health effects of polyphenols.

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A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties.

M Harwood, B Danielewska-Nikiel, J F Borzelleca … (2007)

Quercetin is a naturally-occurring flavonol (a member of the flavonoid family of compounds) that has a long history of consumption as part of the normal human diet. Because a number of biological properties of quercetin may be beneficial to human health, interest in the addition of this flavonol to various traditional food products has been increasing. Prior to the use of quercetin in food applications that would increase intake beyond that from naturally-occurring levels of the flavonol in the typical Western diet, its safety needs to be established or confirmed. This review provides a critical examination of the scientific literature associated with the safety of quercetin. Results of numerous genotoxicity and mutagenicity, short- and long-term animal, and human studies are reviewed in the context of quercetin exposure in vivo. To reconcile results of in vitro studies, which consistently demonstrated quercetin-related mutagenicity to the absence of carcinogenicity in vivo, the mechanisms that lead to the apparent in vitro mutagenicity, and those that ensure absence of quercetin toxicity in vivo are discussed. The weight of the available evidence supports the safety of quercetin for addition to food.

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Author and article information

Journal

Journal ID (nlm-ta): Oxid Med Cell Longev

Journal ID (iso-abbrev): Oxid Med Cell Longev

Journal ID (publisher-id): OMCL

Title: Oxidative Medicine and Cellular Longevity

Publisher: Hindawi Publishing Corporation

ISSN (Print): 1942-0900

ISSN (Electronic): 1942-0994

Publication date (Print): 2016

Publication date (Electronic): 24 January 2016

Volume: 2016

Electronic Location Identifier: 2986796

Affiliations

¹Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA

²Department of Neuroscience, University of Parma Medical School, 43100 Parma, Italy

Author notes

*Lucio G. Costa: lgcosta@ 123456u.washington.edu

Academic Editor: Felipe Dal Pizzol

Article

DOI: 10.1155/2016/2986796

PMC ID: 4745323

PubMed ID: 26904161

SO-VID: c7b8c548-6760-420c-885c-bf7bbc383426

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 27 November 2015

Date revision received : 4 January 2016

Date accepted : 6 January 2016

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Mechanisms of Neuroprotection by Quercetin: Counteracting Oxidative Stress and More

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Abstract

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Most cited references 99

Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders.

Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies.

A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties.

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