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Quercetin supplementation: insight into the potentially harmful outcomes of neurodegenerative prevention

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Abstract

Dietary antioxidant supplements have been considered for the prevention of neuronal oxidative injury and death. Recent studies indicate that excessive antioxidants could exert adverse effects, thereby questioning the safety of prolonged supplementation. The aim of our study was to investigate the effects of quercetin (up to 150 μM), the ubiquitous plant-derived flavonoid and highly potent scavenger of reactive oxygen species (ROS) on healthy P19 neurons, in order to assess the efficacy and safety of its long-term use in neurodegenerative prevention. Although exposure for 24 h to quercetin did not compromise neuronal survival, morphological examination revealed diminished neuronal branching, a finding probably related to an observed decrease in lactate dehydrogenase activity. Using 2′,7′-dichlorofluorescin diacetate and dot–blot analysis, we found reduced basal levels of ROS and 4-hydroxy-2-nonenal, a biomarker of lipid peroxidation, confirming the antioxidative mechanism of quercetin action. Unexpectedly, quercetin also depleted intracellular glutathione content. Reverse transcriptase PCR and western blot analysis showed depletion of total RNA amount and changes in the expression of cell survival regulating genes Bcl-2, p53, and c-fos. Nuclear condensation and caspase-3/7 activity, phenomena related to programmed cell death cascade, were not affected. The potential risk of observed changes indicates that quercetin-enriched supplements should be taken with caution. The diversity of quercetin effects and complexity of possible intracellular interactions between affected genes pointed out the necessity for additional pharmacological and toxicological studies in order to better elucidate the mechanisms of quercetin action and to recognize its potential side effects at higher doses and during long-term administration.

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Abbreviations

ATRA:

all-trans retinoic acid

DCF-DA:

2′,7′-dichlorofluorescin diacetate

DIV:

Days in vitro

HNE:

4-Hydroxy-2-nonenal

MTS:

3-(4,5-Dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium

ROS:

Reactive oxygen species

RFU:

Relative fluorescence unit

References

  • Akhtar RS, Ness JM, Roth KA (2004) Bcl-2 family regulation of neuronal development and neurodegeneration. Biochim Biophys Acta 1644:189–203

    Article  PubMed  CAS  Google Scholar 

  • Antoncic-Svetina M, Sentija D, Cipak A, Milicic D, Meinitzer A, Tatzber F, Andrisic L, Zelzer S, Zarkovic N (2010) Ergometry induces systemic oxidative stress in healthy human subjects. Tohoku J Exp Med 221:43–48

    Article  PubMed  Google Scholar 

  • Arredondo F, Echeverry C, Abin-Carriquiry JA, Blasina F, Antúnez K, Jones DP, Go Y-M, Liang Y-L, Dajas F (2010) After cellular internalization, quercetin causes Nrf2 nuclear translocation, increases glutathione levels, and prevents neuronal death against an oxidative insult. Free Radic Biol Med 49:738–747

    Article  PubMed  CAS  Google Scholar 

  • Bischoff SC (2008) Quercetin: potentials in the prevention and therapy of disease. Curr Opin Clin Nutr Metab Care 11:733–740

    Article  PubMed  CAS  Google Scholar 

  • Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2007) Mortality in randomized trials of antioxidant supplements for primary and secondary prevention. Systematic review and meta-analysis. JAMA 297:842–857

    Article  PubMed  CAS  Google Scholar 

  • Boots AW, Kubben N, Haenen GRMM, Bast A (2003) Oxidized quercetin reacts with thiols rather than with ascorbate: implication for quercetin supplementation. Biochem Biophys Res Commun 308:560–565

    Article  PubMed  CAS  Google Scholar 

  • Boots AW, Li H, Schins RPF, Duffin R, Heemskerk JWM, Bast A, Haenen GRMM (2007) The quercetin paradox. Toxicol Appl Pharmacol 222:89–96

    Article  PubMed  CAS  Google Scholar 

  • Boots AW, Haenen GRMM, Bast A (2008) Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol 585:325–337

    Article  PubMed  CAS  Google Scholar 

  • Choi EJ, Kim G-H (2010) Quercetin accumulation by chronic administration causes the caspase-3 activation in liver and brain of mice. Biofactors 36:216–221

    Article  PubMed  Google Scholar 

  • Choi EJ, Lee BH, Lee K, Chee K-M (2005) Long-term combined administration of quercetin and daidzein inhibits quercetin-induced suppression of glutathione antioxidant defenses. Food Chem Toxicol 43:793–798

    Article  PubMed  CAS  Google Scholar 

  • Čipak Gašparović A, Lovaković T, Žarković N (2010) Oxidative stress and antioxidants: biological response modifiers of oxidative homeostasis in cancer. Period Biol 4:433–439

    Google Scholar 

  • Darley-Usmar VM, Severn A, O’Leary VJ, Rogers M (1991) Treatment of macrophages with oxidized low-density lipoprotein increases their intracellular glutathione content. Biochem J 278:429–434

    PubMed  CAS  Google Scholar 

  • de Boer VCJ, Dihal AA, van der Woude H, Arts ICW, Wolffram S, Alink GM, Rietjens IMCM, Keijer J, Hollman PCH (2005) Tissue distribution of quercetin in rats and pigs. J Nutr 135:1718–1725

    PubMed  Google Scholar 

  • de Martins RP, de Braga HC, da Silva AP, Dalmarco JB, de Bem AF, dos Santos AR, Dafre AL, Pizzolatti MG, Latini A, Aschner M, Farina M (2009) Synergistic neurotoxicity induced by methylmercury and quercetin in mice. Food Chem Toxicol 47:645–649

    Article  Google Scholar 

  • Dianzani MU (2003) 4-Hydroxynonenal from pathology to physiology. Mol Asp Med 24:263–272

    Article  Google Scholar 

  • Emerit J, Edeas M, Bricaire F (2004) Neurodegenerative diseases and oxidative stress. Biomed Pharmacother 58:39–46

    Article  PubMed  CAS  Google Scholar 

  • Estus S, Zaks W, Freeman R, Gruda M, Bravo R, Johnson E (1994) Altered gene expression in neurons during programmed cell death: identification of c-jun as necessary for neuronal apoptosis. J Cell Biol 127:1717–1727

    Article  PubMed  CAS  Google Scholar 

  • Filipe P, Haigle J, Silva JN, Freitas J, Fernandes A, Mazière J-C, Mazière C, Santus R, Morlière P (2004) Anti- and pro-oxidant effects of quercetin in copper-induced low density lipoprotein oxidation. Quercetin as an effective antioxidant against pro-oxidant effects of urate. Eur J Biochem 271:1991–1999

    Article  PubMed  CAS  Google Scholar 

  • Geng Y, Walls KC, Ghosh AP, Akhtar RS, Klocke BJ, Roth KA (2010) Cytoplasmic p53 and activated Bax regulate p53-dependent, transcription-independent neural precursor cell apoptosis. J Histochem Cytochem 58:265–275

    Article  PubMed  CAS  Google Scholar 

  • Guéraud F, Atalay M, Bresgen N, Cipak A, Eckl PM, Huc L, Jouanin I, Siems W, Uchida K (2010) Chemistry and biochemistry of lipid peroxidation products. Free Radic Res 44:1098–1124

    Article  PubMed  Google Scholar 

  • Ham J, Towers E, Gilley J, Terzano S, Randall R (2005) BH3-only proteins: key regulators of neuronal apoptosis. Cell Death Differ 12:1015–1020

    Article  PubMed  CAS  Google Scholar 

  • Ishisaka A, Ichikawa S, Sakakibara H, Piskula MK, Nakamura T, Kato Y, Ito M, Miyamoto K, Tsuji A, Kawai Y, Terao J (2011) Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats. Free Radic Biol Med 51:1329–1336

    Article  PubMed  CAS  Google Scholar 

  • Jakubowicz-Gil J, Rzeski W, Zdzisinska B, Dobrowolski P, Gawron A (2008) Cell death and neuronal arborization upon quercetin treatment in rat neurons. Acta Neurobiol Exp 68:139–146

    Google Scholar 

  • Jazvinšćak Jembrek M, Vuković L, Puhović J, Erhardt J, Oršolić N (2012) Neuroprotective effect of quercetin against hydrogen peroxide-induced oxidative injury in P19 neurons. J Mol Neurosci 47:286–299

    Article  PubMed  Google Scholar 

  • Jung SH, Kim BJ, Lee EH, Osborne NN (2010) Isoquercitrin is the most effective antioxidant in the plant Thuja orientalis and able to counteract oxidative-induced damage to a transformed cell line (RGC-5 cells). Neurochem Int 57:713–721

    Article  PubMed  CAS  Google Scholar 

  • Kelsey NA, Wilkins HM, Linseman DA (2010) Nutraceutical antioxidants as novel neuroprotective agents. Molecules 15:7779–7814

    Article  Google Scholar 

  • Kley N, Chung RY, Fay S, Loeffler JP, Seizinger BR (1992) Repression of the basal c-fos promoter by wild-type p53. Nucl Acid Res 20:4083–4087

    Article  CAS  Google Scholar 

  • Lavoie S, Chen Y, Dalton TP, Gysin R, Cuénod M, Steullet P, Do KQ (2009) Curcumin, quercetin, and tBHQ modulate glutathione levels in actrocytes and neurons: importance of the glutamate cysteine ligase modifier subunit. J Neurochem 108:1410–1422

    Article  PubMed  CAS  Google Scholar 

  • Marinić M, Piantanida I, Rusak G, Žinić M (2006) Interactions of quercetin and its lanthane complex with double stranded DNA/RNA and single stranded RNA: spectrophotometric sensing of poly G. J Inorg Biochem 100:288–298

    Article  PubMed  Google Scholar 

  • Martin KR, Appel CL (2010) Polyphenols as dietary supplements: a double-edged sword. Nutr Diet Suppl 2:1–12

    CAS  Google Scholar 

  • Mennen LI, Walke R, Bennetau-Pelissero C, Scalbert A (2005) Risks and safety of polyphenol consumption. Am J Clin Nutr 81(suppl):326S–329S

    PubMed  CAS  Google Scholar 

  • Montenegro MF, Neto-Neves EM, Dias-Junior CA, Ceron CS, Castro MM, Gomes VA, Kanashiro A, Tanus-Santos JE (2010) Quercetin restores plasma nitrite and nitroso species levels in renovascular hypertension. Naunyn-Schmiedeberg’s Arch Pharmacol 4:293–301

    Article  Google Scholar 

  • Noguchi N (2008) Role of oxidative stress in adaptive responses in special reference to atherogenesis. J Clin Biochem Nutr 43:131–138

    Article  PubMed  Google Scholar 

  • Oršolić N, Benković V, Lisičić D, Đikić D, Erhardt J, Horvat-Knežević A (2010) Protective effects of propolis and related polyphenolic/flavonoid compounds against toxicity induced by irinotecan. Med Oncol 27:1346–1358

    Article  PubMed  Google Scholar 

  • Oršolić N, Gajski G, Garaj-Vrhovac V, Đikić D, Prskalo ZŠ, Sirovina D (2011) DNA-protective effects of quercetin or naringenin in alloxan-induced diabetic mice. Eur J Pharmacol 656:110–118

    Article  PubMed  Google Scholar 

  • Ossola B, Kääriäinen TM, Raasmaja A, Männistö PT (2008) Time-dependent protective and harmful effects of quercetin on 6-OHDA-induced toxicity in neuronal SH-SY5Y cells. Toxicology 250:1–8

    Article  PubMed  CAS  Google Scholar 

  • Ossola B, Kääriäinen TM, Männistö PT (2009) The multiple faces of quercetin in neuroprotection. Expert Opin Drug Saf 8:397–409

    Article  PubMed  CAS  Google Scholar 

  • Pastore A, Federici G, Bertini E, Piemonte F (2003) Analysis of glutathione: implication in redox and detoxification. Clin Chim Acta 333:19–39

    Article  PubMed  CAS  Google Scholar 

  • Pavlica S, Gebhardt R (2010) Protective effects of flavonoids and two metabolites against oxidative stress in neuronal PC12 cells. Life Sci 86:79–86

    Article  PubMed  CAS  Google Scholar 

  • Ristow M, Schmeisser S (2011) Extending life span by increasing oxidative stress. Free Radic Biol Med 51:327–336

    Article  PubMed  CAS  Google Scholar 

  • Ristow M, Zarse K, Oberbach A, Klöting N, Birringer M, Kiehntopf M, Stumvoll M, Kahn CR, Blüher M (2009) Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci USA 106:8665–8670

    Article  PubMed  CAS  Google Scholar 

  • Slemmer JE, Shacka JJ, Sweeney MI, Weber JT (2008) Antioxidants and free radical scavengers for the treatment of stroke, traumatic brain injury and aging. Curr Med Chem 15:404–414

    Article  PubMed  CAS  Google Scholar 

  • Spencer JPE, Rice-Evans C, Williams RJ (2003) Modulation of pro-survival Akt/protein kinase B and ERK1/2 signaling cascades by quercetin and its in vivo metabolites underlie their action on neuronal viability. J Biol Chem 278:34783–34793

    Article  PubMed  CAS  Google Scholar 

  • Steckley D, Karajgikar M, Dale LB, Fuerth B, Swan P, Drummond-Main C, Poulter MO, Ferguson SSG, Strasser A, Cregan SP (2007) Puma is a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis. J Neurosci 27:12989–12999

    Article  PubMed  CAS  Google Scholar 

  • Tedeschi A, Di Giovanni S (2009) The non-apoptotic role of p53 in neuronal biology: enlightening the dark side of the moon. EMBO Rep 10:576–583

    Article  PubMed  CAS  Google Scholar 

  • Turetsky DM, Huettner JE, Gottlieb DI, Goldberg MP, Choi DW (1993) Glutamate receptor-mediated currents and toxicity in embryonal carcinoma cells. J Neurobiol 24:1157–1169

    Article  PubMed  CAS  Google Scholar 

  • Vargas AJ, Burd R (2010) Hormesis and synergy: pathways and mechanisms of quercetin in cancer prevention and management. Nutr Rev 68:418–428

    Article  PubMed  Google Scholar 

  • Yelisyeyeva O, Semen K, Zarkovic N, Kaminskyy D, Lutsyk O, Rybalchenko V (2012) Activation of aerobic metabolism by amaranth oil improves heart rate variability both in athletes and patients with type 2 diabetes mellitus. Arch Physiol Biochem 118:1–11

    Article  Google Scholar 

  • Zarkovic N (2003) 4-Hydroxynonenal as a bioactive marker of pathophysiological processes. Mol Asp Med 24:281–291

    Article  CAS  Google Scholar 

  • Zhang S, Ye J, Dong G (2010) Neuroprotective effect of baicalein on hydrogen peroxide-mediated oxidative stress and mitochondrial dysfunction in PC12 cells. J Mol Neurosci 40:311–320

    Article  PubMed  Google Scholar 

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Acknowledgments

Undifferentiated P19 cells were kindly provided by Dr. J. Pachernik (Prague, Czech Republic). The skilful technical assistance of Sanjica Rak and Lidija Milković is gratefully acknowledged. This study was supported by the Croatian Ministry of Science, Education, and Sports and the COST Action CM1001.

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Authors and Affiliations

  1. Laboratory for Molecular Neuropharmacology, Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka 54, 10 000, Zagreb, Croatia

    Maja Jazvinšćak Jembrek & Josipa Vlainić

  2. Laboratory for Oxidative Stress, Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka 54, Zagreb, Croatia

    Ana Čipak Gašparović & Neven Žarković

  3. Laboratory for Genotoxic Agents, Division of Molecular Biology, Rudjer Boskovic Institute, Bijenicka 54, Zagreb, Croatia

    Lidija Vuković

  4. Department of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, Zagreb, Croatia

    Nada Oršolić

Authors
  1. Maja Jazvinšćak Jembrek
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  2. Ana Čipak Gašparović
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  3. Lidija Vuković
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  4. Josipa Vlainić
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  5. Neven Žarković
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  6. Nada Oršolić
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Correspondence to Maja Jazvinšćak Jembrek.

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Jazvinšćak Jembrek, M., Čipak Gašparović, A., Vuković, L. et al. Quercetin supplementation: insight into the potentially harmful outcomes of neurodegenerative prevention. Naunyn-Schmiedeberg's Arch Pharmacol 385, 1185–1197 (2012). https://doi.org/10.1007/s00210-012-0799-y

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