Elsevier

Biomedicine & Pharmacotherapy

Volume 84, December 2016, Pages 892-908
Biomedicine & Pharmacotherapy

Original article
Bioactive effects of quercetin in the central nervous system: Focusing on the mechanisms of actions

https://doi.org/10.1016/j.biopha.2016.10.011Get rights and content

Abstract

Quercetin, a ubiquitous flavonoid that is widely distributed in plants is classified as a cognitive enhancer in traditional and oriental medicine. The protective effects of quercetin for the treatment of neurodegenerative disorders and cerebrovascular diseases have been demonstrated in both in vitro and in vivo studies. The free radical scavenging activity of quercetin has been well-documented, wherein quercetin has been observed to exhibit protective effects against oxidative stress mediated neuronal damage by modulating the expression of NRF-2 dependent antioxidant responsive elements, and attenuation of neuroinflammation by suppressing NF-κB signal transducer and activator of transcription-1 (STAT-1). Several in vitro and in vivo studies have also shown that quercetin destabilizes and enhances the clearance of abnormal protein such as beta- amyloid peptide and hyperphosphorlyated tau, the key pathological hallmarks of Alzheimer’s disease. Quercetin enhances neurogenesis and neuronal longevity by modulating a broad number of kinase signaling cascades such as phophoinositide 3- kinase (P13-kinase), AKT/PKB tyrosine kinase and Protein kinase C (PKC). Quercetin has also been well reported for its ability to reverse cognitive impairment and memory enhancement during aging. The current review focuses on summarizing the recent findings on the neuroprotective effect of quercetin, its mechanism of action and its possible roles in the prevention of neurological disorders.

Introduction

Quercetin (3,3′,4′,5,7-pentahydroxyflavone) is an unique bi-flavonoid that was first isolated by the physiologist Albert Szent-Györgyi de Nagyrápolt, a Nobel Prize winner for Physiology/Medicine in the year 1936 [1]. The name “quercetin” is derived from the latin name “quercetum” meaning “oak forest, quercus oak”. Vernacular names of quercetin are quercetine, sophretin, memetin [2]. Quercetin is a major component of flavonol subclass and represents 60–75% of total flavonoid intake. It is primarily conjugated with a carbohydrate moiety and forms the backbone of other flavonoids such as rutin, hesperidin, naringenin and tangeritin [3]. Medicinal herbs widely used in traditional ayurvedic, unani, Chinese medicine and Native American remedies contains rich source of quercetin. Multiple pharmacological applications of quercetin, including antioxidant, neuroprotective, anti-viral, anti-cancer, cardiovascular, anti-microbial, anti-inflammatory, hepatoprotective and anti-obesity activities, have made this phytochemical a promising food component for the prevention of lifestyle related disorders [4].

Section snippets

Sources of quercetin

Quercetin is commonly distributed in vegetables, fruits, nuts and grains in association with sugars, phenolic acids and alcohols (Table 1). It is widely distributed in the plant kingdom, specifically in rinds and barks and it is responsible for the bright color of fruits and vegetables. High concentration of quercetin is found in vegetables such as onions (Allium cepa L.), asparagus (Asparagus officinalis L.), and red leaf lettuce (Lactuca sativa L.), while lower concentration has been reported

Chemistry and bioavailability of quercetin

Quercetin is 2-(3,4-dihydroxyphenyl)-trihydroxy-4Hchromen-4-one with molecular weight 302.24, melting point 316 °C, molecular formula C15H10O7. Quercetin consists of five hydroxyl groups whose presence determines the compound’s biological activity and the possible number of derivatives. Quercetin is generally synthesized either according to the Kostanecki’s method or Robinson method. The Kostanecki method involves claisen condensation of 1 2,4-dimethoxy-6-hydroxyacetophenone with

Protective effects on cardiovascular disease

Quercetin protects against coronary heart disease (CHD) by preventing oxidation of LDL (bad) cholesterol. Regular intake of diet rich in quercetin prevents CHD in elderly persons. Scientific evidences illustrated that quercetin exhibited protective effect against cardiovascular diseases such as atherosclerosis, ischemia-reperfusion injury, cardiotoxicity and hypertension [5], [23]. Anti-inflammatory effect of quercetin plays a key role in reducing cardiovascular endangering factors such as

Neuroprotective effect of quercetin: an overview

Brain disorders are considered as the most serious health problems of the modern society. More than 600 disorders afflict the central nervous system, among which neurodegenerative disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease and Huntington's disease the scourge of 21st century [48]. These diseases are growing inevitably as the aging population continues to grow, and pose a severe socio-economic burden to the society. Despite the difference in the

Conclusion

To conclude, quercetin acts as an effective therapeutic agent against various neurodegenerative disorders through the suppression of oxidative stress, inflammation and enhancing neurogenesis. Evidences illustrate quercetin as a potent antioxidant, increases the neuronal survival against a variety of oxidative insults. The presence of inherent number of free hydroxyl groups in the chemical skeleton of quercetin plays an important role for its antioxidant activity. Direct and indirect antioxidant

Acknowledgements

KPD and NS gratefully acknowledge the Bioinformatics Infrastructure Facility provided by the Alagappa University (funded by Department of Biotechnology, Government of India; Grant No. BT/BI/25/015/2012). NS wishes to acknowledge University Grants Commission, New Delhi, India for the financial support through Dr. D.S. Kothari Post Doctoral Fellowship Scheme (No. F.4-2/2006(BSR)/BL/13-14/0345).

References (200)

  • J. Wittig et al.

    Identification of quercetin glucuronides in human plasma by high-performance liquid chromatography–tandem mass spectrometry

    J. Chromatogr. B Biomed. Sci. Appl.

    (2001)
  • M. Russo et al.

    The flavonoid quercetin in disease prevention and therapy: facts and fancies

    Biochem. Pharmacol.

    (2012)
  • J.G.A. Coelho-dos-Reis et al.

    Evaluation of the effects of Quercetin and Kaempherol on the surface of MT-2 cells visualized by atomic force microscopy

    J. Virol. Methods

    (2011)
  • E. Ohnishi et al.

    Quercetin potentiates TNF-induced antiviral activity

    Antiviral Res.

    (1993)
  • D. Fan et al.

    Antiviral and quantitative study of quercetin-3-O-β-D-glucuronide in Polygonum perfoliatum L

    Fitoterapia

    (2011)
  • A. Robaszkiewicz et al.

    Antioxidative and prooxidative effects of quercetin on A549 cells

    Cell. Biol. Int.

    (2007)
  • Y.H. Jung et al.

    Quercetin enhances TRAIL-induced apoptosis in prostate cancer cells via increased protein stability of death receptor 5

    Life Sci.

    (2010)
  • J. Cai et al.

    Oxidative damage and protection of the RPE

    Prog. Retin. Eye Res.

    (2000)
  • N. Chondrogianni et al.

    Anti-ageing and rejuvenating effects of quercetin

    Exp. Gerontol.

    (2010)
  • A. Nieoullon

    Neurodegenerative diseases and neuroprotection: current views and prospects

    J. Appl. Biomed.

    (2011)
  • Y. Gilgun-Sherki et al.

    Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier

    Neuropharmacology

    (2001)
  • F. Arredondo et al.

    After cellular internalization quercetin causes Nrf2 nuclear translocation, increases glutathione levels, and prevents neuronal death against an oxidative insult

    Free Radic. Biol. Med.

    (2010)
  • Y. Shokoohinia et al.

    Quercetin-3-O-β-d-glucopyranoside, a dietary flavonoid, protects PC12 cells from H2O2-induced cytotoxicity through inhibition of reactive oxygen species

    Food Chem.

    (2015)
  • N. Suematsu et al.

    Protective effects of quercetin against hydrogen peroxide-induced apoptosis in human neuronal SH-SY5Y cells

    Neurosci. Lett.

    (2011)
  • M.A. Ansari et al.

    Protective effect of quercetin in primary neurons against Aβ (1–42): relevance to Alzheimer's disease

    J. Nutr. Biochem.

    (2009)
  • L.G. Costa et al.

    Paraoxonase-2 (PON2) in brain and its potential role in neuroprotection

    Neurotoxicology

    (2014)
  • C.K. Glass et al.

    Mechanisms underlying inflammation in neurodegeneration

    Cell

    (2010)
  • M. Lyman et al.

    Neuroinflammation: the role and consequences

    Neurosci. Res.

    (2014)
  • M.T. Heneka et al.

    Neuroinflammation in alzheimer's disease

    Lancet Neurol.

    (2015)
  • M. Naegele et al.

    The good and the bad of neuroinflammation in multiple sclerosis

    Handb. Clin. Neurol.

    (2014)
  • K.G. Hooten et al.

    Protective and toxic neuroinflammation in amyotrophic lateral sclerosis

    Neurotherapeutics

    (2015)
  • J.C. Chen et al.

    Inhibition of iNOS gene expression by quercetin is mediated by the inhibition of I(B kinase, nuclear factor-kappa B and STAT1, and depends on heme oxygenase-1 induction in mouse BV-2 microglia

    Eur. J. Pharmacol.

    (2005)
  • V. Sharma et al.

    Modulation of interleukin-1β mediated inflammatory response in human astrocytes by flavonoids: implications in neuroprotection

    Brain Res. Bull.

    (2007)
  • Z. Sternberg et al.

    Quercetin and interferon-β modulate immune response (s) in peripheral blood mononuclear cells isolated from multiple sclerosis patients

    J. Neuroimmunol.

    (2008)
  • T.J. Chen et al.

    Quercetin inhibition of ROS-dependent and-independent apoptosis in rat glioma C6 cells

    Toxicology

    (2006)
  • M.E. van Meeteren et al.

    Dietary compounds prevent oxidative damage and nitric oxide production by cells involved in demyelinating disease

    Biochem. Pharmacol.

    (2004)
  • K. Szydlowska et al.

    Calcium: ischemia and excitotoxicity

    Cell Calcium

    (2010)
  • M.R. Islam et al.

    In silico QSAR analysis of quercetin reveals its potential as therapeutic drug for Alzheimer's disease

    J. Young Pharmacist.

    (2013)
  • J.B. Harborne

    Flavonoids in the environment: structure-activity relationships

    Prog. Clin. Biol. Res.

    (1987)
  • P. Lakhanpal et al.

    Quercetin: a versatile flavonoid

    Internet J. Med. Update

    (2007)
  • H. Nishimuro et al.

    Estimated daily intake and seasonal food sources of quercetin in Japan

    Nutrients

    (2015)
  • M. Gutzke et al.

    Notes-synthesis of quercetin-2-C14

    J. Org. Chem.

    (1957)
  • I.L. Finar

    Organic chemistry

    (1956)
  • C.A. Williams et al.

    Anthocyanins and other flavonoids

    Nat. Prod. Rep.

    (2004)
  • W.A. Wiczkowski et al.

    Food flavonoids

    Pol. J. Food Nutr. Sci.

    (2004)
  • Q. Chang et al.

    Identification of flavonoids in Hakmeitau beans (Vigna sinensis) by high-performance liquid chromatography-electrospray mass spectrometry (LC-ESI/MS)

    J. Agric. Food Chem.

    (2004)
  • M. Materska et al.

    Antioxidant activity of the main phenolic compounds isolated from hot pepper fruit (Capsicum annuum L.)

    J. Agric. Food Chem.

    (2005)
  • K.M. Janisch et al.

    Properties of quercetin conjugates: modulation of LDL oxidation and binding to human serum albumin

    Free Radic. Res.

    (2004)
  • K. Azuma et al.

    Combination of lipids and emulsifiers enhances the absorption of orally administered quercetin in rats

    J. Agric. Food Chem.

    (2002)
  • J. Guillermo Gormaz et al.

    Cardiovascular disease a target for the pharmacological effects of quercetin

    Curr. Topics Med. Chem.

    (2015)
  • Cited by (168)

    View all citing articles on Scopus
    View full text