Skip to main content
SpringerLink
Log in

Quercetin, kaempferol and biapigenin fromhypericum perforatum are neuroprotective against excitotoxic insults

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

In the present study we investigated the effects of phenolic compounds present inHypericum perforatum against neuronal excitotoxicity and mitochondrial dysfunction. Quercetin, kaemp-ferol and biapigenin significantly reduced neuronal death caused by 100 μM kainate plus 100 μMN-methyl-D-aspartate. The observed neuroprotection was correlated with prevention of delayed calcium deregulation and with the maintenance of mitochondrial transmembrane electric potential. The three compounds were able to reduce mitochondrial lipid peroxidation and loss of mitochondrial transmembrane electric potential caused by oxidative stress induced by ADP plus iron. Moreover, biapigenin was also able to significantly affect mitochondrial bioenergetics and decrease the capacity of mitochondria to accumulate calcium. Taken together, the results suggest that the neuroprotective action induced by quercetin and kaempferol are mainly mediated by antioxidant effects, whereas biapigenin mainly affects mitochondrial bioenergetics and calcium uptake.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

BHT:

butylhydroxytoluene

BSA:

bovine serum albumin

CsA:

cyclosporin A

FCCP:

carbonyl cyanidep-(trifluoromethoxy) phenylhydrazone

KA:

kainic acid

MAP-2:

microtubulle associated protein

m:

Mitochondrial transmembrane potential

NMDA:

N-methyl-D-aspartate

PI:

propidium iodide

ROS:

reactive oxygen species

TPP+ :

tetraphenylphosphonium cation

TBARS:

thiobarbituric acid-reactive species.

References

  • Abreu Rm, DJ Santos and AJ Moreno (2000) Effects of carvedilol and its analog BM-910228 on mitochondrial function and oxidative stress.J. Pharmacol. Exp. Ther. 295, 1022–1030.

    PubMed  CAS  Google Scholar 

  • Angeloni C, JP Spencer, E Leoncini, PL Biagi and S Hrelia (2007) Role of quercetin and its in vivo metabolites in protecting H9c2 cells against oxidative stress.Biochimie 89, 73–82.

    Article  PubMed  CAS  Google Scholar 

  • Bano D, KW Young, CJ Guerin, R Lefeuvre, NJ Rothwell, L Naldini, R Rizzuto, E Carafoli and P Nicotera (2005) Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity.Cell 120, 275–285.

    Article  PubMed  CAS  Google Scholar 

  • Bouchier-Hayes L, L Lartigue and DD Newmeyer (2005) Mitochondria: pharmacological manipulation of cell death.J. Clin. Invest. 115, 2640–2647.

    Article  PubMed  CAS  Google Scholar 

  • Brookes PS, Y Yoon, JL Robotham, MW Anders and SS Sheu (2004) Calcium, ATP, and ROS: a mitochondrial love-hate triangle.Am. J. Physiol. Cell. Physiol. 287, C817-C833.

    Article  PubMed  CAS  Google Scholar 

  • Carafoli E, L Santella, D Branca and M Brini (2001) Generation, control, and processing of cellular calcium signals.Crit. Rev. Biochem. Mol. Biol. 36, 107–260.

    Article  PubMed  CAS  Google Scholar 

  • Chen HS and SA Lipton (2006) The chemical biology of clinically tolerated NMDA receptor antagonists.J. Neurochem. 97, 1611–1626.

    Article  PubMed  CAS  Google Scholar 

  • Cotelle N (2001) Role of flavonoids in oxidative stress.Curr. Top. Med. Chem. 1, 569–590.

    Article  PubMed  CAS  Google Scholar 

  • Dahout-Gonzalez C, C Ramus, EP Dassa, AC Dianoux and G Brandolin (2005) Conformation-dependent swinging of the matrix loop m2 of the mitochondrial Saccharomyces cerevisiae ADP/ATP carrier.Biochemistry 44, 16310–16320.

    Article  PubMed  CAS  Google Scholar 

  • Dajas F, F Rivera-Megret, F Blasina, F Arredondo, JA Abin- Carriquiry, G Costa, C Echeverry, L Lafon, H Heizen, M Ferreira and A Morquio (2003) Neuroprotection by flavonoids.Braz. J. Med. Biol. Res. 36, 1613–1620.

    Article  PubMed  CAS  Google Scholar 

  • De Paola R, C Muia, E Mazzon, T Genovese, C Crisafulli, M Menegazzi, AP Caputi, H Suzuki and S Cuzzocrea (2005) Effects of Hypericum perforatum extract in a rat model of ischemia and reperfusion injury.Shock 24, 255–263.

    Article  PubMed  Google Scholar 

  • Dias ACP, FA Tomas-Barberan, M Fernandes-Ferreira and F Ferreres (1998) Unusual flavonoids produced by callus of Hypericum perforatum.Phytochemistry 48, 1165–1168.

    Article  CAS  Google Scholar 

  • Dorta DJ, AA Pigoso, FE Mingatto, T Rodrigues, IM Prado, AF Helena, SA Uyemura, AC Santos and C Curti (2005) The interaction of flavonoids with mitochondria: effects on energetic processes.Chem. Biol. Interact. 152, 67–78.

    Article  PubMed  CAS  Google Scholar 

  • Dubinsky JM, N Brustovetsky and R LaFrance (2004) Protective roles of CNS mitochondria.J. Bioenerg. Biomembr. 36, 299–302.

    Article  PubMed  CAS  Google Scholar 

  • Duchen MR (2004) Mitochondria in health and disease: perspectives on a new mitochondrial biology.Mol. Aspects Med. 25, 365–451.

    PubMed  CAS  Google Scholar 

  • Estabrook RW (1967) Mitochondrial respiratory control and the polarographic measurement of ADP:O ratios.Meth. Enzymol. 10, 41–47.

    Article  CAS  Google Scholar 

  • Ferreira FM, CM Palmeira, MJ Matos, R Seica and MS Santos (1999) Decreased susceptibility to lipid peroxidation of Goto-Kakizaki rats: relationship to mitochondrial antioxidant capacity.Life Sci. 65, 1013–1025.

    Article  PubMed  CAS  Google Scholar 

  • Filipe P, V Lanca, JN Silva, P Morliere, R Santus and A Fernandes (2001) Flavonoids and urate antioxidant interplay in plasma oxidative stress.Mol. Cell. Biochem. 221, 79–87.

    Article  PubMed  CAS  Google Scholar 

  • Halestrap AP (2006) Calcium, mitochondria and reperfusion injury: a pore way to die.Biochem. Soc. Trans. 34, 232–237.

    Article  PubMed  CAS  Google Scholar 

  • Isaev NK, NA Andreeva, EV Stel’mashuk and DB Zorov (2005) Role of mitochondria in the mechanisms of glutamate toxicity.Biochemistry (Mosc.) 70, 611–618.

    Article  CAS  Google Scholar 

  • Ishige K, D Schubert and Y Sagara (2001) Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms.Free Radic. Biol. Med. 30, 433–446.

    Article  PubMed  CAS  Google Scholar 

  • Jovanovic SV and MG Simic (2000) Antioxidants in nutrition.Ann. NY Acad. Sci. 899, 326–334.

    Article  PubMed  CAS  Google Scholar 

  • Kamo N, M Muratsugu, R Hongoh and Y Kobatake (1979) Membrane potential of mitochondria measured with an electrode sensitive to tetraphenyl phosphonium and relationship between proton electrochemical potential and phosphorylation potential in steady state.J. Membr. Biol. 49, 105–121.

    Article  PubMed  CAS  Google Scholar 

  • Kiedrowski L and E Costa (1995) Glutamate-induced destabilization of intracellular calcium concentration homeostasis in cultured cerebellar granule cells: role of mitochondria in calcium buffering.Mol. Pharmacol. 47, 140–147.

    PubMed  CAS  Google Scholar 

  • Kristian T and BK Siesjo (1998) Calcium in ischemic cell death.Stroke 29, 705–718.

    PubMed  CAS  Google Scholar 

  • Kushnareva YE, SE Wiley, MW Ward, AY Andreyev and AN Murphy (2005) Excitotoxic injury to mitochondria isolated from cultured neurons.J. Biol. Chem. 280, 28894–28902.

    Article  PubMed  CAS  Google Scholar 

  • Lafon-Cazal M, S Pietri, M Culcasi and J Bockaert (1993) NMDA-dependent superoxide production and neurotoxicity.Nature 364, 535–537.

    Article  PubMed  CAS  Google Scholar 

  • Lipton SA and PA Rosenberg (1994) Excitatory amino acids as a final common pathway for neurologic disorders.N. Engl. J. Med. 330, 613–622.

    Article  PubMed  CAS  Google Scholar 

  • Mattson MP and G Kroemer (2003) Mitochondria in cell death: novel targets for neuroprotection and cardioprotection.Trends Mol. Med. 9, 196–205.

    Article  PubMed  CAS  Google Scholar 

  • Montal M (1998) Mitochondria, glutamate neurotoxicity and the death cascade.Biochim. Biophys. Acta 1366, 113–126.

    Article  PubMed  CAS  Google Scholar 

  • Montero M, CD Lobaton, E Hernandez-Sanmiguel, J Santodomingo, L Vay, A Moreno and J Alvarez (2004) Direct activation of the mitochondrial calcium uniporter by natural plant flavonoids.Biochem. J. 384, 19–24.

    Article  PubMed  CAS  Google Scholar 

  • Moreira PI, MS Santos, A Moreno, AC Rego and C Oliveira (2002) Effect of amyloid-β peptide on permeability transition pore: a comparative study.J. Neurosci. Res. 69, 257–267.

    Article  PubMed  CAS  Google Scholar 

  • Moreira PI, MS Santos, C Sena, R Seica and CR Oliveira (2005) Insulin protects against amyloid-β peptide toxicity in brain mitochondria of diabetic rats.Neurobiol. Dis. 18, 628–637.

    Article  PubMed  CAS  Google Scholar 

  • Nicholls DG (2002) Mitochondrial function and dysfunction in the cell: its relevance to aging and aging-related disease. Int.J. Biochem. Cell. Biol. 34, 1372–1381.

    Article  CAS  Google Scholar 

  • Nicholls D.G (2004) Mitochondrial dysfunction and glutamate excitotoxicity studied in primary neuronal cultures.Curr. Mol. Med. 4, 149–177.

    Article  PubMed  CAS  Google Scholar 

  • Nicholls DG and SL Budd (1998) Mitochondria and neuronal glutamate excitotoxicity.Biochim. Biophys. Acta 1366, 97–112.

    Article  PubMed  CAS  Google Scholar 

  • Nicholls DG and MW Ward (2000) Mitochondrial membrane potential and neuronal glutamate excitotoxicity: mortality and millivolts.Trends Neurosci. 23, 166–174.

    Article  PubMed  CAS  Google Scholar 

  • Oliveira PJ, R Seica, MP Coxito, AP Rolo, CM Palmeira, MS Santos and AJ Moreno (2003) Enhanced permeability transition explains the reduced calcium uptake in cardiac mitochondria from streptozotocin-induced diabetic rats.FEBS Lett. 554, 511–514.

    Article  PubMed  CAS  Google Scholar 

  • Oliveira PJ, JA Bjork, MS Santos, RL Leino, MK Froberg, AJ Moreno and KB Wallace (2004) Carvedilol-mediated antioxidant protection against doxorubicin-induced cardiac mitochondrial toxicity.Toxicol. Appl. Pharmacol. 200, 159–168.

    Article  PubMed  CAS  Google Scholar 

  • Ozgova S, J Hermanek and I Gut (2003) Different antioxidant effects of polyphenols on lipid peroxidation and hydroxyl radicals in the NADPH-, Fe-ascorbate- and Fe-microsomal systems.Biochem. Pharmacol. 66, 1127–1137.

    Article  PubMed  CAS  Google Scholar 

  • Peng IW and SM Kuo (2003) Flavonoid structure affects the inhibition of lipid peroxidation in Caco-2 intestinal cells at physiological concentrations.J. Nutr. 133, 2184–2187.

    PubMed  CAS  Google Scholar 

  • Peng TI and JT Greenamyre (1998) Privileged access to mitochondria of calcium influx through N-methyl-D-aspartate receptors.Mol. Pharmacol. 53, 974–980.

    PubMed  CAS  Google Scholar 

  • Rego AC, MW Ward and DG Nicholls (2001) Mitochondria control AMPA/kainate receptor-induced cytoplasmic calcium deregulation in rat cerebellar granule cells.J. Neurosci. 21, 1893–1901.

    PubMed  CAS  Google Scholar 

  • Rego AC, NM Monteiro, AP Silva, J Gil, JO Malva and CR Oliveira (2003) Mitochondrial apoptotic cell death and moderate superoxide generation upon selective activation of non-desensitizing AMPA receptors in hippocampal cultures.J. Neurochem. 86, 792–804.

    Article  PubMed  CAS  Google Scholar 

  • Reynolds IJ and TG Hastings (1995) Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation.J. Neurosci. 15, 3318–3327.

    PubMed  CAS  Google Scholar 

  • Rice-Evans C (2001) Flavonoid antioxidants.Curr. Med. Chem. 8, 797–807.

    PubMed  CAS  Google Scholar 

  • Samhan-Arias AK, FJ Martín-Romero and C Gutiérrez-Merino (2004) Kaempferol blocks oxidative stress in cerebellar granule cells and reveals a key role for reactive oxygen species production at the plasma membrane in the commitment to apoptosis.Free. Radic. Biol. Med. 37, 48–61.

    Article  PubMed  CAS  Google Scholar 

  • Santos AC, SA Uyemura, JL Lopes, JN Bazon, FE Mingatto and C Curti (1998) Effect of naturally occurring flavonoids on lipid peroxidation and membrane permeability transition in mitochondria.Free Radic. Biol. Med. 24, 1455–1461.

    Article  PubMed  CAS  Google Scholar 

  • Saris NE and E Carafoli (2005) A historical review of cellular calcium handling, with emphasis on mitochondria.Biochemistry (Mosc.) 70, 187–194.

    Article  CAS  Google Scholar 

  • Schroeter H, JP Spencer, C Rice-Evans and RJ Williams (2001) Flavonoids protect neurons from oxidized low-density-lipoprotein- induced apoptosis involving c-Jun N-terminal kinase (JNK), c-Jun and caspase-3.Biochem. J. 358, 547–557.

    Article  PubMed  CAS  Google Scholar 

  • Silva AP, JO Malva, AF Ambrosio, AJ Salgado, AP Carvalho and CM Carvalho (2001) Role of kainate receptor activation and desensitization on the [Ca2+]i changes in cultured rat hippocampal neurons.J. Neurosci. Res. 65, 378–386.

    Article  PubMed  CAS  Google Scholar 

  • Silva BA, ACP Dias, F Ferreres, JO Malva and CR Oliveira (2004) Neuroprotective effect ofH. perforatum extracts on β-amyloid-induced neurotoxicity.Neurotox. Res. 6, 119–130.

    Article  PubMed  Google Scholar 

  • Silva BA, F Ferreres, JO Malva and ACP Dias (2005) Phytochemical and antioxidant characterization ofHypericum perforatum alcoholic extracts.Food Chem. 90, 157–167.

    Article  CAS  Google Scholar 

  • Simonyi A, Q Wang, RL Miller, M Yusof, PB Shelat, AY Sun and GY Sun (2005) Polyphenols in cerebral ischemia: novel targets for neuroprotection.Mol. Neurobiol. 31, 135–147.

    Article  PubMed  CAS  Google Scholar 

  • Stout AK, HM Raphael, BI Kanterewicz, E Klann and IJ Reynolds (1998) Glutamate-induced neuron death requires mitochondrial calcium uptake.Nat. Neurosci. 1, 366–373.

    Article  PubMed  CAS  Google Scholar 

  • Vander Heiden MG and CB Thompson (1999) Bcl-2 proteins: regulators of apoptosis or of mitochondrial homeostasis?Nat. Cell Biol. 1, E209-E216.

    Article  PubMed  CAS  Google Scholar 

  • Vergun O, AI Sobolevsky, MV Yelshansky, J Keelan, BI Khodorov and MR Duchen (2001) Exploration of the role of reactive oxygen species in glutamate neurotoxicity in rat hippocampal neurones in culture.J. Physiol. 531, 147–163.

    Article  PubMed  CAS  Google Scholar 

  • Vieira HL, D Haouzi, C El Hamel, E Jacotot, AS Belzacq, C Brenner and G Kroemer (2000) Permeabilization of the mitochondrial inner membrane during apoptosis: impact of the adenine nucleotide translocator.Cell Death Differ. 7, 1146–1154.

    Article  PubMed  CAS  Google Scholar 

  • Wang CN, CW Chi, YL Lin, CF Chen and YJ Shiao (2001) The neuroprotective effects of phytoestrogens on amyloid-β protein- induced toxicity are mediated by abrogating the activation of caspase cascade in rat cortical neurons.J. Biol. Chem. 276, 5287–5295.

    Article  PubMed  CAS  Google Scholar 

  • Weber JT (2004) Calcium homeostasis following traumatic neuronal injury.Curr. Neurovasc. Res. 1, 151–171.

    Article  PubMed  Google Scholar 

  • Won SJ, DY Kim and BJ Gwag (2002) Cellular and molecular pathways of ischemic neuronal death.J. Biochem. Mol. Biol. 35, 67–86.

    PubMed  CAS  Google Scholar 

  • Zhao B (2005) Natural antioxidants for neurodegenerative diseases.Mol. Neurobiol. 31, 283–293.

    Article  PubMed  CAS  Google Scholar 

  • Zheng J and VD Ramirez (2000) Inhibition of mitochondrial proton F0F1-ATPase/ATP synthase by polyphenolic phytochemicals.Br. J. Pharmacol. 130, 1115–1123.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    Bruno Silva, Paulo J. Oliveira & JOÃO O. Malva

  2. Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    JOÃO O. Malva

  3. Department of Biology, University of Minho, Braga, Portugal

    Bruno Silva & Alberto Dias

Authors
  1. Bruno Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paulo J. Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alberto Dias
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. JOÃO O. Malva
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to JOÃO O. Malva.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Silva, B., Oliveira, P.J., Dias, A. et al. Quercetin, kaempferol and biapigenin fromhypericum perforatum are neuroprotective against excitotoxic insults. neurotox res 13, 265–279 (2008). https://doi.org/10.1007/BF03033510

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03033510

Keywords

Search

Navigation