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Neuroprotective effects of digested polyphenols from wild blackberry species

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European Journal of Nutrition Aims and scope Submit manuscript

Abstract

Purpose

Blackberry ingestion has been demonstrated to attenuate brain degenerative processes with the benefits ascribed to the (poly)phenolic components. The aim of this work was to evaluate the neuroprotective potential of two wild blackberry species in a neurodegeneration cell model and compare them with a commercial variety.

Methods

This work encompasses chemical characterization before and after an in vitro digestion and the assessment of neuroprotection by digested metabolites. Some studies targeting redox/cell death systems were also performed to assess possible neuroprotective molecular mechanisms.

Results

The three blackberry extracts presented some quantitative differences in polyphenol composition that could be responsible for the different responses in the neurodegeneration cell model. Commercial blackberry extracts were ineffective but both wild blackberries, Rubus brigantinus and Rubus vagabundus, presented neuroprotective effects. It was verified that a diminishment of intracellular ROS levels, modulation of glutathione levels and activation of caspases occurred during treatment. The last effect suggests a preconditioning effect since caspase activation was not accompanied by diminution in cell death and loss of functionality.

Conclusions

This is the first time that metabolites obtained from an in vitro digested food matrix, and tested at levels approaching the concentrations found in human plasma, have been described as inducing an adaptative response.

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References

  1. Lau FC, Shukitt-Hale B, Joseph JA (2006) Beneficial effects of berry fruit polyphenols on neuronal and behavioral aging. J Agric Food Chem 86:2251–2255

    Article  CAS  Google Scholar 

  2. Beking K, Vieira A (2010) Flavonoid intake and disability-adjusted life years due to Alzheimer’s and related dementias: a population-based study involving twenty-three developed countries. Public Health Nutr 13:1403–1409

    Article  Google Scholar 

  3. Wimo A, Jonsson L, Gustavsson A, McDaid D, Ersek K, Georges J, Gulacsi L, Karpati K, Kenigsberg P, Valtonen H (2011) The economic impact of dementia in Europe in 2008-cost estimates from the Eurocode project. Int J Geriatr Psychiatry 26:825–832

    Article  CAS  Google Scholar 

  4. Maiese K, Chong ZZ, Hou J, Shang YC (2009) New strategies for Alzheimer’s disease and cognitive impairment. Oxid Med Cell Longev 2:279–289

    Article  Google Scholar 

  5. Dumont M, Beal MF (2011) Neuroprotective strategies involving ROS in Alzheimer disease. Free Radic Biol Med 51:1014–1026

    Article  CAS  Google Scholar 

  6. Williams P, Sorribas A, Howes MJR (2011) Natural products as a source of Alzheimer’s drug leads. Nat Prod Rep 28:48–77

    Article  CAS  Google Scholar 

  7. de Rijk MC, Breteler MM, den Breeijen JH, Launer LJ, Grobbee DE, van der Meche FG, Hofman A (1997) Dietary antioxidants and Parkinson disease. The Rotterdam study. Arch Neurol 54:762–765

    Article  Google Scholar 

  8. Di Matteo V, Esposito E (2003) Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Curr Drug Targets CNS Neurol Disord 2:95–107

    Article  Google Scholar 

  9. Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB (2006) Fruit and vegetable juices and Alzheimer’s disease: the Kame project. Am J Med 119:751–759

    Article  CAS  Google Scholar 

  10. Seeram NP (2008) Berry fruits: compositional elements, biochemical activities, and the impact of their intake on human health, performance, and disease. J Agric Food Chem 56:627–629

    Article  CAS  Google Scholar 

  11. Shukitt-Hale B, Lau FC, Joseph JA (2008) Berry fruit supplementation and the aging brain. J Agric Food Chem 56:636–641

    Article  CAS  Google Scholar 

  12. Dai J, Patel JD, Mumper RJ (2007) Characterization of blackberry extract and its antiproliferative and anti-inflammatory properties. J Med Food 10:258–265

    Article  CAS  Google Scholar 

  13. Wang SY, Jiao H (2000) Scavenging capacity of berry crops on superoxide radicals, hydrogen peroxide, hydroxyl radicals, and singlet oxygen. J Agric Food Chem 48:5677–5684

    Article  CAS  Google Scholar 

  14. Shukitt-Hale B, Cheng V, Joseph JA (2009) Effects of blackberries on motor and cognitive function in aged rats. Nutr Neurosci 12:135–140

    Article  CAS  Google Scholar 

  15. Joseph JA, Kowatch MA, Maki T, Roth GS (1990) Selective cross-activation/inhibition of second messenger systems and the reduction of age-related deficits in the muscarinic control of dopamine release from perifused rat striata. Brain Res 537:40–48

    Article  CAS  Google Scholar 

  16. Rutz S, Majchrzak M, Siedschlag V, Barbelivien A, Harati H, Rothmaier AK, Feuerstein TJ, Jackisch R, Cassel JC (2009) The modulation of striatal dopamine release correlates with water-maze performance in aged rats. Neurobiol Aging 30:957–972

    Article  CAS  Google Scholar 

  17. Ramassamy C (2006) Emerging role of polyphenolic compounds in the treatment of neurodegenerative diseases: a review of their intracellular targets. Eur J Pharmacol 545:51–64

    Article  CAS  Google Scholar 

  18. Castroviejo S (ed) (1986–2007) Flora Ibérica. Plantas vasculares de la Península Ibérica e Islas Baleares. Real Jardín Botánico, CSIC, Madrid

  19. Tavares L, Fortalezas S, Carrilho C, McDougall GJ, Stewart D, Ferreira RB, Santos CN (2010) Antioxidant and antiproliferative properties of strawberry tree tissues. J Berry Res 1:3–12

    CAS  Google Scholar 

  20. Tavares L, Figueira I, Macedo D, McDougall GJ, Leitão MC, Vieira HLA, Stewart D, Alves PM, Ferreira RB, Santos CN (2012) Neuroprotective effect of blackberry (Rubus sp.) polyphenols is potentiated after simulated gastrointestinal digestion. Food Chem 131:1443–1452

    Article  CAS  Google Scholar 

  21. Tavares L, Carrilho D, Tyagi M, Barata D, Serra AT, Duarte CMM, Duarte RO, Feliciano RP, Bronze MR, Chicau P, Espírito-Santo MD, Ferreira RB, dos Santos CN (2010) Antioxidant capacity of Macaronesian traditional medicinal plants. Molecules 15:2576–2592

    Article  CAS  Google Scholar 

  22. Queiroga CS, Almeida AS, Martel C, Brenner C, Alves PM, Vieira HL (2010) Glutathionylation of adenine nucleotide translocase induced by carbon monoxide prevents mitochondrial membrane permeabilization and apoptosis. J Biol Chem 285:17077–17088

    Article  CAS  Google Scholar 

  23. Wang H, Joseph JA (1999) Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader. Free Radic Biol Med 27:612–616

    Article  CAS  Google Scholar 

  24. Wolfe KL, Liu RH (2007) Cellular antioxidant activity (CAA) assay for assessing antioxidants, foods, and dietary supplements. J Agric Food Chem 55:8896–8907

    Article  CAS  Google Scholar 

  25. Kand’ar R, Zakova P, Lotkova H, Kucera O, Cervinkova Z (2007) Determination of reduced and oxidized glutathione in biological samples using liquid chromatography with fluorimetric detection. J Pharm Biomed Anal 43:1382–1387

    Article  Google Scholar 

  26. Bensadoun A, Weinstein D (1976) Assay of proteins in the presence of interfering materials. Anal Biochem 70:241–250

    Article  CAS  Google Scholar 

  27. Wolfe KL, Kang X, He X, Dong M, Zhang Q, Liu RH (2008) Cellular antioxidant activity of common fruits. J Agric Food Chem 56:8418–8426

    Article  CAS  Google Scholar 

  28. McDougall GJ, Fyffe S, Dobson P, Stewart D (2005) Anthocyanins from red wine-their stability under simulated gastrointestinal digestion. Phytochemistry 66:2540–2548

    Article  CAS  Google Scholar 

  29. McDougall GJ, Fyffe S, Dobson P, Stewart D (2007) Anthocyanins from red cabbage-stability to simulated gastrointestinal digestion. Phytochemistry 68:1285–1294

    Article  CAS  Google Scholar 

  30. Perez-Vicente A, Gil-Izquierdo A, Garcia-Viguera C (2002) In vitro gastrointestinal digestion study of pomegranate juice phenolic compounds, anthocyanins, and vitamin C. J Agric Food Chem 50:2308–2312

    Article  CAS  Google Scholar 

  31. Gil-Izquierdo A, Gil MI, Ferreres F (2002) Effect of processing techniques at industrial scale on orange juice antioxidant and beneficial health compounds. J Agric Food Chem 50:5107–5114

    Article  CAS  Google Scholar 

  32. Deaville ER, Green RJ, Mueller-Harvey I, Willoughby I, Frazier RA (2007) Hydrolyzable tannin structures influence relative globular and random coil protein binding strengths. J Agric Food Chem 55:4554–4561

    Article  CAS  Google Scholar 

  33. Mertz C, Cheynier V, Gunata Z, Brat P (2007) Analysis of phenolic compounds in two blackberry species (Rubus glaucus and Rubus adenotrichus) by high-performance liquid chromatography with diode array detection and electrospray ion trap mass spectrometry. J Agric Food Chem 55:8616–8624

    Article  CAS  Google Scholar 

  34. Mullen W, Yokota T, Lean MEJ, Crozier A (2003) Analysis of ellagitannins and conjugates of ellagic acid and quercetin in raspberry fruits by LC-MSn. Phytochemistry 64:617–624

    Article  CAS  Google Scholar 

  35. Ayoub NA (2010) A trimethoxyellagic acid glucuronide from Conocarpus erectus leaves: isolation, characterization and assay of antioxidant capacity. Pharm Biol 48:328–332

    Article  CAS  Google Scholar 

  36. Manach C, Williamson G, Morand C, Scalbert A, Remesy C (2005) Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr 81:230S–242S

    CAS  Google Scholar 

  37. Jung KA, Kwak MK (2010) The Nrf2 system as a potential target for the development of indirect antioxidants. Molecules 15:7266–7291

    Article  CAS  Google Scholar 

  38. Lee C, Park GH, Kim CY, Jang JH (2011) [6]-Gingerol attenuates beta-amyloid-induced oxidative cell death via fortifying cellular antioxidant defense system. Food Chem Toxicol 49:1261–1269

    Article  CAS  Google Scholar 

  39. Lu YH, Su MY, Huang HY, Lin L, Yuan CG (2010) Protective effects of the citrus flavanones to PC12 cells against cytotoxicity induced by hydrogen peroxide. Neurosci Lett 484:6–11

    Article  CAS  Google Scholar 

  40. 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  CAS  Google Scholar 

  41. Ballatori N, Krance SM, Notenboom S, Shi S, Tieu K, Hammond CL (2009) Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem 390:191–214

    Article  CAS  Google Scholar 

  42. Dalle-Donne I, Rossi R, Giustarini D, Colombo R, Milzani A (2007) S-glutathionylation in protein redox regulation. Free Radic Biol Med 43:883–898

    Article  CAS  Google Scholar 

  43. Artal-Sanz M, Tavernarakis N (2005) Proteolytic mechanisms in necrotic cell death and neurodegeneration. FEBS Lett 579:3287–3296

    Article  CAS  Google Scholar 

  44. Spencer JP, Schroeter H, Kuhnle G, Srai SK, Tyrrell RM, Hahn U, Rice-Evans C (2001) Epicatechin and its in vivo metabolite, 3′-O-methyl epicatechin, protect human fibroblasts from oxidative-stress-induced cell death involving caspase-3 activation. Biochem J 354:493–500

    Article  CAS  Google Scholar 

  45. Garnier P, Ying W, Swanson RA (2003) Ischemic preconditioning by caspase cleavage of poly(ADP-ribose) polymerase-1. J Neurosci 23:7967–7973

    CAS  Google Scholar 

  46. McLaughlin B, Hartnett KA, Erhardt JA, Legos JJ, White RF, Barone FC, Aizenman E (2003) Caspase 3 activation is essential for neuroprotection in preconditioning. Proc Natl Acad Sci USA 100:715–720

    Article  CAS  Google Scholar 

  47. Tanaka H, Yokota H, Jover T, Cappuccio I, Calderone A, Simionescu M, Bennett MV, Zukin RS (2004) Ischemic preconditioning: neuronal survival in the face of caspase-3 activation. J Neurosci 24:2750–2759

    Article  CAS  Google Scholar 

  48. Mandel S, Amit T, Reznichenko L, Weinreb O, Youdim MB (2006) Green tea catechins as brain-permeable, natural iron chelators-antioxidants for the treatment of neurodegenerative disorders. Mol Nutr Food Res 50:229–234

    Article  CAS  Google Scholar 

  49. Andres-Lacueva C, Shukitt-Hale B, Galli RL, Jauregui O, Lamuela-Raventos RM, Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and may enhance memory. Nutr Neurosci 8:111–120

    Article  CAS  Google Scholar 

  50. Kalt W, Blumberg JB, McDonald JE, Vinqvist-Tymchuk MR, Fillmore SAE, Graf BA, O’Leary JM, Milbury PE (2008) Identification of anthocyanins in the liver, eye, and brain of blueberry-fed pigs. J Agric Food Chem 56:705–712

    Article  CAS  Google Scholar 

  51. Mullen W, Larcombe S, Arnold K, Welchman H, Crozier A (2009) Use of accurate mass full scan mass spectrometry for the analysis of anthocyanins in berries and berry-fed tissues. J Agric Food Chem 58:3910–3915

    Article  Google Scholar 

  52. Milbury PE, Kalt W (2010) Xenobiotic metabolism and berry flavonoid transport across the blood-brain barrier. J Agric Food Chem 58:3950–3956

    Article  CAS  Google Scholar 

  53. Son TG, Camandola S, Mattson MP (2008) Hormetic dietary phytochemicals. Neuromolecular Med 10:236–246

    Article  CAS  Google Scholar 

  54. Cho MJ, Howard LR, Prior RL, Clark JR (2004) Flavonoid glycosides and antioxidant capacity of various blackberry, blueberry and red grape genotypes determined by high-performance liquid chromatography/mass spectrometry. J Sci Food Agric 84:1771–1782

    Article  Google Scholar 

  55. Jordheim M, Enerstvedt KH, Andersen OM (2011) Identification of cyanidin 3-O-beta-(6″-(3-Hydroxy-3-methylglutaroyl)glucoside) and other anthocyanins from wild and cultivated blackberries. J Agric Food Chem 59:7436–7440

    Article  CAS  Google Scholar 

  56. Gasperotti M, Masuero D, Vrhovsek U, Guella G, Mattivi F (2010) Profiling and accurate quantification of Rubus ellagitannins and ellagic acid conjugates using direct UPLC-Q-TOF HDMS and HPLC-DAD analysis. J Agric Food Chem 58:4602–4616

    Article  CAS  Google Scholar 

  57. Kool MM, Comeskey DJ, Cooney JM, McGhie TK (2010) Structural identification of the main ellagitannins of a boysenberry (Rubus loganbaccus × baileyanus Britt.) extract by LC-ESI-MS/MS,MALDI-TOF-MS and NMR spectroscopy. Food Chem 119:1535–1543

    Article  CAS  Google Scholar 

  58. Cho MJ, Howard LR, Prior RL, Clark JR (2005) Flavonol glycosides and antioxidant capacity of various blackberry and blueberry genotypes determined by high-performance liquid chromatography/mass spectrometry. J Sci Food Agric 85:2149–2158

    Article  CAS  Google Scholar 

  59. Hager TJ, Howard LR, Liyanage R, Lay JO, Prior RL (2008) Ellagitannin composition of blackberry as determined by HPLC-ESI-MS and MALDI-TOF-MS. J Agric Food Chem 56:661–669

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by Fundação para a Ciência e a Tecnologia through grant PEst-OE/EQB/LA0004/2011 and also by financial support of CS (SRFH/BPD/26562/2006) and LT (SFRH/BD/37382/2007) and by Action Cost 863 (by the financial support of LT short-term scientific mission). DS and GM were supported by Scottish Government Research and Science Division and ClimaFruit (Interreg IVb-North Sea Region Programme). Moreover, this work was also supported by EUBerry FP7-KBBE-2010-265942). We would like to acknowledge Pedro Oliveira for providing commercial blackberry fruits from Herdade Experimental da Fataca. We also would like thank to Carlos Aguiar from CIMO, Instituto Politécnico de Bragança for helping us to identify and collect the wild species, to Cristina Silva Pereira for providing access to HPLC and M. Cristina Leitão for the HPLC technical support.

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Correspondence to Cláudia N. Santos.

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Tavares, L., Figueira, I., McDougall, G.J. et al. Neuroprotective effects of digested polyphenols from wild blackberry species. Eur J Nutr 52, 225–236 (2013). https://doi.org/10.1007/s00394-012-0307-7

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  • DOI: https://doi.org/10.1007/s00394-012-0307-7

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