Archives of Toxicology

, Volume 84, Issue 2, pp 89–97 | Cite as

Comparative study of quercetin and its two glycoside derivatives quercitrin and rutin against methylmercury (MeHg)-induced ROS production in rat brain slices

  • Caroline Wagner
  • Alessandra P. Vargas
  • Daniel H. Roos
  • Ademir F. Morel
  • Marcelo Farina
  • Cristina W. Nogueira
  • Michael Aschner
  • João B. Rocha
Inorganic Compounds

Abstract

The hypothesis that methylmercury (MeHg) potently induces formation of reactive oxygen species (ROS) in the brain is supported by observations on the neuroprotective effects of various classes of antioxidants. Flavonoids have been reported to possess divalent metal chelating properties, antioxidant activities and to readily permeate the blood–brain barrier. They can also provide neuroprotection in a wide array of cellular and animal models of neurological diseases. Paradoxically, in vivo administration of quercetin displays unexpected synergistic neurotoxic effect with MeHg. Considering this controversy and the limited data on the interaction of MeHg with other flavonoids, the potential protective effect of quercetin and two of its glycoside analogs (i.e., rutin and quercitrin) against MeHg toxicity were evaluated in rat cortical brain slices. MeHg (100 μM) caused lipid peroxidation and ROS generation. Quercitrin (10 μg/mL) and quercetin (10 μg/mL) protected mitochondria from MeHg (5 μM)-induced changes. In contrast, rutin did not afford a significant protective effect against MeHg (100 μM)-induced lipid peroxidation and ROS production in cortical brain slices. MeHg-generated ROS in cortical slices was dependent upon an increase in intracellular Ca2+ levels, because the over-production of MeHg-induced H2O2 in mitochondria occurred with a concomitant increase in Ca2+ transient. Here, we have extended the characterization of mechanisms associated with the neuroprotective effects of quercetin against MeHg-induced toxicity in isolated mitochondria, by performing an array of parallel studies in brain slices. We provide novel data establishing that (1) Ca2+ plays a central role in MeHg toxicity and (2) in brain slices MeHg induces mitochondrial oxidative stress both via direct interaction with mitochondria (as previously reported in in vitro studies) as well as via mitochondria-independent (or indirect) mechanisms.

Keywords

MeHg toxicity Quercetin Quercitrin Rutin ROS Mitochondria 

Supplementary material

204_2009_482_MOESM1_ESM.doc (34 kb)
Supplementary material 1 (DOC 34 kb)

References

  1. Allen JW, Mutkus LA, Aschner M (2001) Methylmercury-mediated inhibition of 3H-D-aspartate transport in cultured astrocytes is reversed by the antioxidant catalase. Brain Res 902:92–100CrossRefPubMedGoogle Scholar
  2. Allen JW, Shanker G, Tan KH, Aschner M (2002) The consequences of methylmercury exposure on interactive functions between astrocytes and neurons. Neurotoxicology 23:755–759CrossRefPubMedGoogle Scholar
  3. Araragi S, Kondoh M, Kawas M, Saito S, Higashimoto M, Sato M (2003) Mercuric chloride induces apoptosis via a mitochondrial-dependent pathway in human leukemia cells. Toxicology 184:1–9CrossRefPubMedGoogle Scholar
  4. Aschner M, Yao CP, Allen JW, Tan KH (2000) Methylmercury alters glutamate transport in astrocyte. Neurochem Int 37:199–206CrossRefPubMedGoogle Scholar
  5. Aschner M, Syversen T, Souza DO, Rocha JBT, Farina M (2007) Involvement of glutamate and reactive oxygen species in methylmercury neurotoxicity. Braz J Med Biol Res 40:285–291CrossRefPubMedGoogle Scholar
  6. Brustovetsky N, Dubinsky JM (2000) Dual responses of CNS mitochondria to elevated calcium. J Neurosci 20:103–113PubMedGoogle Scholar
  7. Cai Q, Rahn RO, Zhang R (1997) Dietary flavonoids, quercetin, luteolin and genistein reduce oxidative DNA damage and lipid peroxidation and quench free radicals. Cancer Lett 119:99–107CrossRefPubMedGoogle Scholar
  8. Choi DW (1992) Excitotoxic cell death. J Neurobiol 23:1261–1276CrossRefPubMedGoogle Scholar
  9. Clarkson TW, Magos L, Myers GJ (2003) The toxicology of mercury-current exposures and clinical manifestations. New Engl J Med 349:1731–1737CrossRefPubMedGoogle Scholar
  10. Cotelle N (2001) Role of flavonoids in oxidative stress. Curr Top Med Chem 1:569–590CrossRefPubMedGoogle Scholar
  11. Dajas F, Rivera-Megre F, Blasina F, Arredondo F, Abin-Carriquiry JA, Costa G, Echeverry C, Lafon L, Heizen H, Ferreira M, Morquio A (2003) Neuroprotection by flavonoids. Braz J Med Biol Res 36:1613–1620CrossRefPubMedGoogle Scholar
  12. Denny MF, Hare MF, Atchison WD (1993) Methylmercury alters intrasynaptosomal concentrations of endogenous polyvalent cations. Toxicol Appl Pharmacol 122:222–232CrossRefPubMedGoogle Scholar
  13. Dreiem A, Seegal RF (2007) Methylmercury-induced changes in mitochondrial function in striatal synaptosomes are calcium-dependent and ROS-independent. Neurotoxicology 28:720–726CrossRefPubMedGoogle Scholar
  14. Dubinsky JM, Levi Y (1998) Calcium-induced activation of the mitochondrial permeability transition in hippocampal neurons. J Neurosci Res 53:728–741CrossRefPubMedGoogle Scholar
  15. Farina M, Franco JL, Ribas CM, Meotti FC, Missau FC, Pizzolatti MG, Dafre AL, Santos AR (2005) Protective effects of Polygala paniculata extract against methylmercury-induced neurotoxicity in mice. J Pharm Pharmacol 57:1503–1508CrossRefPubMedGoogle Scholar
  16. Fiskum G, Rosenthal RE, Vereczky V (2004) Protection against ischemic brain injury by inhibition of mitochondrial oxidative stress. J Bioenerg Biomembr 36:347–352CrossRefPubMedGoogle Scholar
  17. Fonfria E, Vilaro MT, Babot Z, Rodriguez-Farre E, Sunol C (2005) Mercury compounds disrupt neuronal glutamate transport in cultured mouse cerebellar granule cells. J Neurosci Res 79:545–553CrossRefPubMedGoogle Scholar
  18. Franco JL, Braga HC, Stringari J, Missau FC, Posser T, Mendes BG, Leal RB, Santos AR, Dafre AL, Pizzolatti MG, Farina M (2007) Mercurial-induced hydrogen peroxide generation in mouse brain mitochondria: protective effects of quercetin. Chem Res Toxicol 20:1919–1926CrossRefPubMedGoogle Scholar
  19. Grotto D, de Castro MM, Barcelos GRM, Garcia SC, Barbosa F (2009) Low level and sub-chronic exposure to methylmercury induces hypertension in rats: nitric oxide depletion and oxidative damage as possible mechanisms. Arch Toxicol 83:653–662CrossRefPubMedGoogle Scholar
  20. Gugliucci A, Stahl AJ (1995) Low density lipoprotein oxidation is inhibited by extracts of Ilex paraguariensis. Biochem Mol Biol Int 35:47–56PubMedGoogle Scholar
  21. Gupta R, Singh M, Sharma A (2003) Neuroprotective effect of antioxidants on ischaemia and reperfusion-induced cerebral injury. Pharmacol Res 48:209–215CrossRefPubMedGoogle Scholar
  22. Hansson MJ, Månsson R, Morota S, Uchino H, Kallur T, Sumi T, Ishii N, Shimazu M, Keep MF, Jegorov A, Elmér E (2008) Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition. Free Radic Biol Med 45:284–294CrossRefPubMedGoogle Scholar
  23. Hollman PC, Katan MB (1999) Dietary flavonoids: intake, health effects and bioavailability. Food Chem Toxicol 37:937–942CrossRefPubMedGoogle Scholar
  24. InSug O, Datar S, Koch CJ, Shapiro IM, Shenker BJ (1997) Mercuric compounds inhibit human monocyte function by inducing apoptosis: evidence for formation of reactive oxygen species, development of mitochondrial membrane permeability transition and loss of reductive reserve. Toxicology 124:211–224CrossRefPubMedGoogle Scholar
  25. Kaariaien TM, Piltonen M, Ossola B (2008) Lack of robust protective effect of quercetin in two types of 6-hydroxydopamine-induced parkinsonian models in rats and dopaminergic cell cultures. Brain Res 1203:149–159CrossRefGoogle Scholar
  26. Komulainen H, Bondy SC (1987) Increased free intrasynaptosomal Ca2+ by neurotoxic organometals: distinctive mechanisms. Toxicol Appl Pharmacol 88:77–86CrossRefPubMedGoogle Scholar
  27. Lifshitz J, Sullivan PG, Hovda DA (2004) Mitochondrial damage and dysfunction in traumatic brain injury. Mitochondrion 4:705–713CrossRefPubMedGoogle Scholar
  28. Limke TL, Heidemann SR, Atchison WD (2004) Disruption of intraneuronal divalent cation regulation by methylmercury: are specific targets involved in altered neuronal development and cytotoxicity in methylmercury poisoning? Neurotoxicology 25:741–760CrossRefPubMedGoogle Scholar
  29. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  30. Mande S, Amit T, Reznichenk L, Weinre O, Youdim MB (2006) Green tea catechins as brain-permeable, natural iron chelators-antioxidants for the treatment of neurodegenerative disorders. Mol Nutr Food Res 50:229–234CrossRefGoogle Scholar
  31. Martins RP, Braga HC, 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 47:645–649CrossRefGoogle Scholar
  32. Marty MS, Atchison WD (1997) Pathways mediating Ca2+ entry in rat cerebellar granule cells following in vitro exposure to methyl mercury. Toxicol Appl Pharmacol 147:319–330CrossRefPubMedGoogle Scholar
  33. Meotti FC, Fachinetto R, Maffi LC, Missau FC, Pizzolatti MG, Rocha JB, Santos AR (2007) Antinociceptive action of myricitrin: involvement of the K+ and Ca2+ channels. Eur J Pharmacol 567:198–205CrossRefPubMedGoogle Scholar
  34. Morel AF, Dias GO, Porto C, Simionatto C, Stuker CZ, Dalcol II (2006) Antimicrobial activity of extractives of Solidago microglossa. Fitoterapia 77:453–455CrossRefPubMedGoogle Scholar
  35. Mori N, Yasutake A, Hirayama K (2007) Comparative study of activities in reactive oxygen species production/defense system in mitochondria of rat brain and liver, and their susceptibility to methylmercury toxicity. Arch Toxicol 81:769–776CrossRefPubMedGoogle Scholar
  36. Pereira RP, Fachinetto R, de Souza Prestes A, Puntel RL, Santos da Silva GN, Heinzmann BM, Boschetti TK, Athayde ML, Bürger ME, Morel AF, Morsch VM, Rocha JB (2009) Antioxidant effects of different extracts from Melissa officinalis, Matricaria recutita and Cymbopogon citratus. Neurochem Res 34:973–983CrossRefPubMedGoogle Scholar
  37. Reichl FX, Esters M, Simon S, Seiss M, Kehe K, Kleinsasser N, Folwaczny M, Glas J, Hickel R (2006a) Cell death effects of resin-based dental material compounds and mercurials in human gingival fibroblasts. Arch Toxicol 80:370–377CrossRefPubMedGoogle Scholar
  38. Reichl FX, Simon S, Esters M, Seiss M, Kehe K, Kleinsasser N, Hickel R (2006b) Cytotoxicity of dental composite (co)monomers and the amalgam component Hg(2+) in human gingival fibroblasts. Arch Toxicol 80:465–472CrossRefPubMedGoogle Scholar
  39. Rice-Evans CA, Miller NJ, Paganga G (1996) Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 20:933–956CrossRefPubMedGoogle Scholar
  40. Roos DH, Puntel RL, Santos MM, Souza DO, Farina M, Nogueira CW, Aschner M, Burger ME, Barbosa NB, Rocha JB (2009) Guanosine and synthetic organoselenium compounds modulate methylmercury-induced oxidative stress in rat brain cortical slices: Involvement of oxidative stress and glutamatergic system. Toxicol In Vitro 23:302–307CrossRefPubMedGoogle Scholar
  41. Saija A, Scalese M, Lanza M, Marzullo D, Bonina F, Castelli F (1995) Flavonoids as antioxidant agents: importance of their interaction with biomembranes. Free Radic Biol Med 19:481–486CrossRefPubMedGoogle Scholar
  42. Santamaría A, Santamaría D, Díaz-Muñoz M, Espinoza-González V, Ríos C (1997) Effects of N omega-nitro-l-arginine and l-arginine on quinolinic acid-induced lipid peroxidation. Toxicol Lett 93:117–124CrossRefPubMedGoogle Scholar
  43. Schmid K, Sassen A, Staudenmaier R, Kroemer S, Reichl FX, Harréus U, Hagen R, Kleinsasser N (2007) Mercuric dichloride induces DNA damage in human salivary gland tissue cells and lymphocytes. Arch Toxicol 81:759–767CrossRefPubMedGoogle Scholar
  44. Shanker G, Aschner M (2003) Methylmercury-induced reactive oxygen species formation in neonatal cerebral astrocytic cultures is attenuated by antioxidants. Mol Brain Res 110:85–91CrossRefPubMedGoogle Scholar
  45. Shenker BJ, Guo TL, Shapiro IM (1999) Induction of apoptosis in human T-cells by methyl mercury: temporal relationship between mitochondrial dysfunction and loss of reductive reserve. Toxicol Appl Pharmacol 157:23–35CrossRefPubMedGoogle Scholar
  46. Sirois JE, Atchison WD (2000) Methylmercury affects multiple subtypes of calcium channels in rat cerebellar granule cells. Toxicol Appl Pharmacol 167:1–11CrossRefPubMedGoogle Scholar
  47. Spanos GA, Wrolstad RE (1992) Phenolic of apple, pear, and white grape juices and their changes with processing and storage—a rewiew. J Agric Food Chem 40:1478–1487CrossRefGoogle Scholar
  48. Sudati JH, Fachinetto R, Pereira RP, Boligon AA, Athayde ML, Soares FA, Barbosa NV, Rocha JB (2009) In vitro antioxidant activity of Valeriana officinalis against different neurotoxic agents. Neurochem Res 34:1372–1379CrossRefPubMedGoogle Scholar
  49. Valko M, Morris H, Cronin MTD (2005) Metals, toxicity and oxidative stress. Curr Med Chem 12:1161–1208CrossRefPubMedGoogle Scholar
  50. Verity MA, Brown WJ, Cheung M (1975) Organic mercurial encephalopathy: in vivo and in vitro effects of methyl mercury on synaptosomal respiration. J Neurochem 25:759–766CrossRefPubMedGoogle Scholar
  51. Wagner C, Fachinetto R, Dalla Corte CL, Brito VB, Severo D, Costa Dias G, Morel AF, Nogueira CW, Rocha JB (2006) Quercitrin, a glycoside form of quercetin, prevents lipid peroxidation in vitro. Brain Res 1107:192–198CrossRefPubMedGoogle Scholar
  52. Wang H, Joseph JA (1999) Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader. Free Radic Biol Med 27:612–616CrossRefPubMedGoogle Scholar
  53. Yee S, Choi BH (1994) Methylmercury poisoning induces oxidative stress in the mouse brain. Exp Mol Pathol 60:188–196CrossRefPubMedGoogle Scholar
  54. Youdim KA, Qaiser MZ, Begley DJ, Rice-Evans CA, Abbott NJ (2004) Flavonoid permeability across an in situ model of the blood–brain barrier. Free Radic Biol Med 36:592–604CrossRefPubMedGoogle Scholar
  55. Zbarsky V, Datla KP, Parkar S, Rai DK, Aruoma OI, Dexter DT (2005) Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson’s disease. Free Radic Res 39:1119–1125CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Caroline Wagner
    • 1
  • Alessandra P. Vargas
    • 1
  • Daniel H. Roos
    • 1
  • Ademir F. Morel
    • 1
  • Marcelo Farina
    • 2
  • Cristina W. Nogueira
    • 1
  • Michael Aschner
    • 3
  • João B. Rocha
    • 1
  1. 1.Centro de Ciências Naturais e Exatas, Departamento de QuímicaUniversidade Federal de Santa MariaSanta MariaBrazil
  2. 2.Departamento de Bioquímica, Centro de Ciências BiológicasUniversidade Federal de FlorianópolisFlorianópolisBrazil
  3. 3.Department of Pediatrics and PharmacologyVanderbilt University School of MedicineNashvilleUSA

Personalised recommendations