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Published Online: 15 November 2013

Blueberry (Vaccinium virgatum) Leaf Extracts Protect Against Aβ-Induced Cytotoxicity and Cognitive Impairment

Publication: Journal of Medicinal Food
Volume 16, Issue Number 11

Abstract

The ethylacetate (EtOAc) fraction of blueberry leaf extract was investigated to examine the in vivo antiamnesic effects against amyloid β protein (Aβ)-induced learning and memory deficit. The fraction showed the highest antioxidant activities, and the generation of intracellular reactive oxygen species was significantly decreased. Cell viability assays revealed the in vitro cytoprotective effects of the fraction, and the cytoplasmic lactate dehydrogenase release into the medium was dose-dependently inhibited. In addition, a chlorogenic acid was identified as a predominant phenolic compound by high-performance liquid chromatography analysis. Antiamnesic effects were evaluated by using in vivo the Y-maze and passive avoidance tests, and preadministration of the fraction attenuated Aβ-induced memory impairment in both in vivo experiments. Acetylcholinesterase prepared from mice brain was inhibited by the fraction, and malondialdehyde generation in the brain homogenate was also decreased. These findings suggest that the EtOAc fraction of blueberry leaf extract could possess a wide range of physiological effects against neurodegenerative diseases.

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References

1.
Choi SJKim MJHeo HJKim JKJun WJKim HKKim EKKim MOCho HYHwang HJKim YJShin DH. Ameliorative effect of 1,2-benzenedicarboxylic acid dinonyl ester against amyloid beta peptide-induced neurotoxicityAmyloid20091615-24. 1. Choi SJ, Kim MJ, Heo HJ, Kim JK, Jun WJ, Kim HK, Kim EK, Kim MO, Cho HY, Hwang HJ, Kim YJ, Shin DH: Ameliorative effect of 1,2-benzenedicarboxylic acid dinonyl ester against amyloid beta peptide-induced neurotoxicity. Amyloid 2009;16:15–24.
2.
Munoz DGFeldman DG. Causes of Alzheimer's diseaseCan Med Assoc J200016265-72. 2. Munoz DG, Feldman DG: Causes of Alzheimer's disease. Can Med Assoc J 2000;162:65–72.
3.
Rottkamp CARaina AKZhu XGaier EBush AIAtwood CSChevion MPerry GSmith MA. Redox-active iron mediates amyloid-beta toxicityFree Radic Biol Med200130447-450. 3. Rottkamp CA, Raina AK, Zhu X, Gaier E, Bush AI, Atwood CS, Chevion M, Perry G, Smith MA: Redox-active iron mediates amyloid-beta toxicity. Free Radic Biol Med 2001;30:447–450.
4.
Butterfield DADrake JPocernich CCastegna A. Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid β-peptideTrends Mol Med20017548-554. 4. Butterfield DA, Drake J, Pocernich C, Castegna A: Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid β-peptide. Trends Mol Med 2001;7:548–554.
5.
Mecocci MDPMacGarvey MSUBeal MF. Oxidative damage to mitochondrial DNA is increases in Alzheimer's diseaseAnn Neurol199436747-751. 5. Mecocci MDP, MacGarvey MSU, Beal MF: Oxidative damage to mitochondrial DNA is increases in Alzheimer's disease. Ann Neurol 1994;36:747–751.
6.
Behl CDavis JBLesley RSchubert D. Hydrogen peroxide mediates amyloid β protein toxicityCell199477817-827. 6. Behl C, Davis JB, Lesley R, Schubert D: Hydrogen peroxide mediates amyloid β protein toxicity. Cell 1994;77:817–827.
7.
Fiers WBeyaert RDeclercq WVandenabeele P. More than one way to die: apoptosis, necrosis and reactive oxygen damageOncogene1999187719-7730. 7. Fiers W, Beyaert R, Declercq W, Vandenabeele P: More than one way to die: apoptosis, necrosis and reactive oxygen damage. Oncogene 1999;18:7719–7730.
8.
Zana MJanka ZKálmán J. Oxidative stress: a bridge between Down's syndrome and Alzheimer's diseaseNeurobiol Aging200728648-676. 8. Zana M, Janka Z, Kálmán J: Oxidative stress: a bridge between Down's syndrome and Alzheimer's disease. Neurobiol Aging 2007;28:648–676.
9.
Findeis MA. The role of amyloid β peptide 42 in Alzheimer's diseasePharmacol Ther2007116266-286. 9. Findeis MA: The role of amyloid β peptide 42 in Alzheimer's disease. Pharmacol Ther 2007;116:266–286.
10.
Gowing ERoher AEWoods ASCotter RJChaney MLittle SPBall MJ. Chemical characterization of A beta 17–42 peptide, a component of diffuse amyloid deposits of Alzheimer diseaseJ Biol Chem199426910987-10990. 10. Gowing E, Roher AE, Woods AS, Cotter RJ, Chaney M, Little SP, Ball MJ: Chemical characterization of A beta 17–42 peptide, a component of diffuse amyloid deposits of Alzheimer disease. J Biol Chem 1994;269:10987–10990.
11.
Kubo TNishimura SKumagae YKaneko I. In vivo conversion of racemized β-amyloid ([D-Ser26]Aβ1–40) to truncated and toxic fragments ([D-Ser26]Aβ25–35/40) and fragment presence in the brains of Alzheimer's patientsJ Neurosci Res200270474-483. 11. Kubo T, Nishimura S, Kumagae Y, Kaneko I: In vivo conversion of racemized β-amyloid ([D-Ser26]Aβ1–40) to truncated and toxic fragments ([D-Ser26]Aβ25–35/40) and fragment presence in the brains of Alzheimer's patients. J Neurosci Res 2002;70:474–483.
12.
Butterfield DAReed TNewman SFSultana R. Roles of amyloid β-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer's disease and mild cognitive impairmentFree Radic Biol Med200743658-677. 12. Butterfield DA, Reed T, Newman SF, Sultana R: Roles of amyloid β-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer's disease and mild cognitive impairment. Free Radic Biol Med 2007;43:658–677.
13.
Casley CSLand JMSharpe MAClark JBDuchem MRCanevari L. β-Amyloid fragment 25–35 causes mitochondrial dysfunction in primary cortical neuronsNeurobiol Dis200210258-267. 13. Casley CS, Land JM, Sharpe MA, Clark JB, Duchem MR, Canevari L: β-Amyloid fragment 25–35 causes mitochondrial dysfunction in primary cortical neurons. Neurobiol Dis 2002;10:258–267.
14.
Lee KWKim YJKim DOLee HJLee CY. Major phenolics in apple and their contribution to the total antioxidant capacityJ Agric Food Chem2003516516-6520. 14. Lee KW, Kim YJ, Kim DO, Lee HJ, Lee CY: Major phenolics in apple and their contribution to the total antioxidant capacity. J Agric Food Chem 2003;51:6516–6520.
15.
Westwood MNTemperate-Zone PomologyTimber PressPortland, OR, USA1988100-101. 15. Westwood MN: Temperate-Zone Pomology. Timber Press, Portland, OR, USA, 1988, pp. 100–101.
16.
Su MSChien PJ. Antioxidant activity, anthocyanins, and phenolics of rabbiteye blueberry (Vaccinium ashei) fluid products as affected by fermentationFood Chem2007104182-187. 16. Su MS, Chien PJ: Antioxidant activity, anthocyanins, and phenolics of rabbiteye blueberry (Vaccinium ashei) fluid products as affected by fermentation. Food Chem 2007;104:182–187.
17.
Martineau LCCouture ASpoor DBenhaddou-Andaloussi AHarris CMeddah BLeduc CBurt AVuong TLe PMPrentki MBennett SAArnason JTHaddad PS. Anti-diabetic properties of the canadian lowbush blueberry Vaccinium angustifolium AitPhytomedicine200613612-623. 17. Martineau LC, Couture A, Spoor D, Benhaddou-Andaloussi A, Harris C, Meddah B, Leduc C, Burt A, Vuong T, Le PM, Prentki M, Bennett SA, Arnason JT, Haddad PS: Anti-diabetic properties of the canadian lowbush blueberry Vaccinium angustifolium Ait. Phytomedicine 2006;13:612–623.
18.
Papandreoua MADimakopouloub ALinardakia ZICordopatisb PKlimis-Zacasc DMargaritya MLamari FN. Effect of a polyphenol-rich wild blueberry extract on cognitive performance of mice, brain antioxidant markers and acetylcholinesterase activityBehav Brain Res2009198352-358. 18. Papandreoua MA, Dimakopouloub A, Linardakia ZI, Cordopatisb P, Klimis-Zacasc D, Margaritya M, Lamari FN: Effect of a polyphenol-rich wild blueberry extract on cognitive performance of mice, brain antioxidant markers and acetylcholinesterase activity. Behav Brain Res 2009;198:352–358.
19.
Li YCLi BXGeng LJ. Hypolipidemic and antioxidant effects of total flavonoids from blueberry leavesEur Food Res Technol2011233897-903. 19. Li YC, Li BX, Geng LJ: Hypolipidemic and antioxidant effects of total flavonoids from blueberry leaves. Eur Food Res Technol 2011;233:897–903.
20.
Piljac-Zegarac JBelscak APiljac A. Antioxidant capacity and polyphenolic content of blueberry (Vaccinium corymbosum L.) leaf infusionsJ Med Food200912608-614. 20. Piljac-Zegarac J, Belscak A, Piljac A: Antioxidant capacity and polyphenolic content of blueberry (Vaccinium corymbosum L.) leaf infusions. J Med Food 2009;12:608–614.
21.
Hicks JMuhammad ASaleem ACuerrier AAranson TJohn CLK. Quantification of chlorogenic acid and hyperoside directly from crude blueberry (Vaccinium angustifolium) leaf extract by NMR spectroscopy analysis: single-laboratory validationJ AOAC Int2012951406-1411. 21. Hicks J, Muhammad A, Saleem A, Cuerrier A, Aranson T, John CLK: Quantification of chlorogenic acid and hyperoside directly from crude blueberry (Vaccinium angustifolium) leaf extract by NMR spectroscopy analysis: single-laboratory validation. J AOAC Int 2012;95:1406–1411.
22.
Chang STWu JHWang SYKang PLYang NSShyur LF. Antioxidant activity of extracts from Acacia confusa bark and heartwoodJ Agric Food Chem2001493420-3424. 22. Chang ST, Wu JH, Wang SY, Kang PL, Yang NS, Shyur LF: Antioxidant activity of extracts from Acacia confusa bark and heartwood. J Agric Food Chem 2001;49:3420–3424.
23.
Kim JKChoi SJCho HYHwang HJKim YJLim STKim CJKim HKPeterson SShin DH. Protective effects of kaempferol (3,4′,5,7-tetrahydroxyflavone) against amyloid beta peptide (Aβ)-induced neurotoxicity in ICR miceBiosci Biotech Biochem201074397-401. 23. Kim JK, Choi SJ, Cho HY, Hwang HJ, Kim YJ, Lim ST, Kim CJ, Kim HK, Peterson S, Shin DH: Protective effects of kaempferol (3,4′,5,7-tetrahydroxyflavone) against amyloid beta peptide (Aβ)-induced neurotoxicity in ICR mice. Biosci Biotech Biochem 2010;74:397–401.
24.
Heo HJLee CY. Strawberry and its anthocyanins reduce oxidative stress-induced apoptosis in PC12 cellsJ Agric Food Chem2005531984-1989. 24. Heo HJ, Lee CY: Strawberry and its anthocyanins reduce oxidative stress-induced apoptosis in PC12 cells. J Agric Food Chem 2005;53:1984–1989.
25.
Yan JJCho JYKim HSKim KLJang JSHuh SOSuh HWKim YHSong DK. Protection against β-amyloid peptide toxicity in vivo with long-term administration of ferulic acidBr J Pharmacol200113389-96. 25. Yan JJ, Cho JY, Kim HS, Kim KL, Jang JS, Huh SO, Suh HW, Kim YH, Song DK: Protection against β-amyloid peptide toxicity in vivo with long-term administration of ferulic acid. Br J Pharmacol 2001;133:89–96.
26.
Kim MJChoi SJLim STLim HKHeo HJKim EKJun WJCho HYKim YJShin DH. Ferulic acid supplementation prevents trimethyltin-induced cognitive deficits in miceBiosci Biotech Biochem2007711063-1106. 26. Kim MJ, Choi SJ, Lim ST, Lim HK, Heo HJ, Kim EK, Jun WJ, Cho HY, Kim YJ, Shin DH: Ferulic acid supplementation prevents trimethyltin-induced cognitive deficits in mice. Biosci Biotech Biochem 2007;71:1063–1106.
27.
Lu JZhang YLWu DMLuo LSun DXShan Q. Ursolic acid ameliorates cognition deficits and attenuates oxidative damage in the brain of senescent mice induced by D-galactoseBiochem Pharmacol2007741078-1090. 27. Lu J, Zhang YL, Wu DM, Luo L, Sun DX, Shan Q: Ursolic acid ameliorates cognition deficits and attenuates oxidative damage in the brain of senescent mice induced by D-galactose. Biochem Pharmacol 2007;74:1078–1090.
28.
Wang HHelliwell K. Determination of flavonols in green and black tea leaf and green tea infusions by high-performance liquid chromatographyFood Res Int200134223-227. 28. Wang H, Helliwell K: Determination of flavonols in green and black tea leaf and green tea infusions by high-performance liquid chromatography. Food Res Int 2001;34:223–227.
29.
Heo HJLee CY. Phenolic phytochemicals in cabbage inhibit amyloid beta protein-induced neurotoxicityLWT Food Sci Technol200639330-336. 29. Heo HJ, Lee CY: Phenolic phytochemicals in cabbage inhibit amyloid beta protein-induced neurotoxicity. LWT Food Sci Technol 2006;39:330–336.
30.
Kim SSPark RYJeon HJKwon YSChun W. Neuroprotective effects of 3,5-dicaffeoylquinic acid on hydrogen peroxide-induced cell death in SH-SY5Y cellsPhytother Res200519243-245. 30. Kim SS, Park RY, Jeon HJ, Kwon YS, Chun W: Neuroprotective effects of 3,5-dicaffeoylquinic acid on hydrogen peroxide-induced cell death in SH-SY5Y cells. Phytother Res 2005;19:243–245.
31.
Almeida IFFernandes ELima JLFCValentao PAndrade PBSeabra RMCosta PCBahia MF. Oxygen and nitrogen reactive species are effectively scavenged by Eucalyptus globulus leaf water extractJ Med Food20091275-183. 31. Almeida IF, Fernandes E, Lima JLFC, Valentao P, Andrade PB, Seabra RM, Costa PC, Bahia MF: Oxygen and nitrogen reactive species are effectively scavenged by Eucalyptus globulus leaf water extract. J Med Food 2009;12:75–183.
32.
Bernatoniene JMasteikova RMajiene DSavickas AKevelaitis EBernatoniene RDvorackova KCivinskiene GLekas RVitkevicius KPeciura R. Free radical-scavenging activities of Crataegus monogyna extractsMedicina200844706-712. 32. Bernatoniene J, Masteikova R, Majiene D, Savickas A, Kevelaitis E, Bernatoniene R, Dvorackova K, Civinskiene G, Lekas R, Vitkevicius K, Peciura R: Free radical-scavenging activities of Crataegus monogyna extracts. Medicina 2008;44:706–712.
33.
Silva BADias ACFerreres FMalva JOOliveira CR. Neuroprotective effect of H. perforatum extracts on β-amyloid-induced neurotoxicityNeurotox Res20046119-130. 33. Silva BA, Dias AC, Ferreres F, Malva JO, Oliveira CR: Neuroprotective effect of H. perforatum extracts on β-amyloid-induced neurotoxicity. Neurotox Res 2004;6:119–130.
34.
Ahn EHKim DWShin MJKwon SWKim YNKim DSLim SSKim JPark JSEum WSHwang HSChoi SY. Chlorogenic acid improves neuroprotective effect of PEP-1-ribosomal protein S3 against ischemic insultExp Neurobiol201221172-172. 34. Ahn EH, Kim DW, Shin MJ, Kwon SW, Kim YN, Kim DS, Lim SS, Kim J, Park JS, Eum WS, Hwang HS,Choi SY: Chlorogenic acid improves neuroprotective effect of PEP-1-ribosomal protein S3 against ischemic insult. Exp Neurobiol 2012;21:172–172.
35.
Oboh GAgunloye OMAkinyemi AJAdemiluyi AOAdefegha SA. Comparative study on the inhibitory effect of caffeic and chlorogenic acids on key enzymes linked to Alzheimer's disease and some pro-oxidant induced oxidative stress in rats' brain-in vitroNeurochem Res201338413-419. 35. Oboh G, Agunloye OM, Akinyemi AJ, Ademiluyi AO, Adefegha SA: Comparative study on the inhibitory effect of caffeic and chlorogenic acids on key enzymes linked to Alzheimer's disease and some pro-oxidant induced oxidative stress in rats' brain-in vitro. Neurochem Res 2013;38:413–419.
36.
Shena WQia RZhang JWang ZWang HHua CZhao YBie MWang YFu YChend MLua D. Chlorogenic acid inhibits LPS-induced microglial activation and improves survival of dopaminergic neuronsBrain Res Bull201288487-494. 36. Shena W, Qia R, Zhang J, Wang Z, Wang H, Hua C, Zhao Y, Bie M, Wang Y, Fu Y, Chend M, Lua D: Chlorogenic acid inhibits LPS-induced microglial activation and improves survival of dopaminergic neurons. Brain Res Bull 2012;88:487–494.
37.
Kwon SHLee HKKim JAHong SIKim HCJo THPark YILee CKKim YBLee SYJang CG. Neuroprotective effects of chlorogenic acid on scopolamine-induced amnesia via anti-acetylcholinesterase and anti-oxidative activities in miceEur J Pharmacol2010649210-217. 37. Kwon SH, Lee HK, Kim JA, Hong SI, Kim HC, Jo TH, Park YI, Lee CK, Kim YB, Lee SY, Jang CG: Neuroprotective effects of chlorogenic acid on scopolamine-induced amnesia via anti-acetylcholinesterase and anti-oxidative activities in mice. Eur J Pharmacol 2010;649:210–217.
38.
Baum LNg A. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal modelsJ Alzheimers Dis20046367-377. 38. Baum L, Ng A: Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal models. J Alzheimers Dis 2004;6:367–377.
39.
Geula CMesulam M. Special properties of cholinesterases in the cerebral cortex of Alzheimer's diseaseBrain Res1989498185-189. 39. Geula C, Mesulam M: Special properties of cholinesterases in the cerebral cortex of Alzheimer's disease. Brain Res 1989;498:185–189.
40.
Khan MTOrhan ISenol FSKartal MSener BDvorská MSmejkal KSlapetová T. Cholinesterase inhibitory activities of some flavonoid derivatives and chosen xanthone and their molecular docking studiesChem Biol Interact2009181383-389. 40. Khan MT, Orhan I, Senol FS, Kartal M, Sener B, Dvorská M, Smejkal K, Slapetová T: Cholinesterase inhibitory activities of some flavonoid derivatives and chosen xanthone and their molecular docking studies. Chem Biol Interact 2009;181:383–389.
41.
Shen YSheng RZhang JHe QYang BHu Y. 2-Phenoxy-indan-1-one derivatives as acetylcholinesterase inhibitors: A study on the importance of modifications at the side chain on the activityBioorgan Med Chem2008157646-7653. 41. Shen Y, Sheng R, Zhang J, He Q, Yang B, Hu Y: 2-Phenoxy-indan-1-one derivatives as acetylcholinesterase inhibitors: A study on the importance of modifications at the side chain on the activity. Bioorgan Med Chem 2008;15:7646–7653.
42.
Jeong HYKim JYLee HKHa DTSong KSBae KHSeong YH. Leaf and stem of Vitis amurensis and its active components protect against amyloid β protein (25–35)-induced neurotoxicityArch Pharm Res2010331655-1664. 42. Jeong HY, Kim JY, Lee HK, Ha DT, Song KS, Bae KH, Seong YH: Leaf and stem of Vitis amurensis and its active components protect against amyloid β protein (25–35)-induced neurotoxicity. Arch Pharm Res 2010;33:1655–1664.
43.
Banji DBanji OJFAbbagoni SHayath SKambam SChiluka VL. Amelioration of behavioral aberrations and oxidative markers by green tea extract in valproate induced autism in animalsBrain Res20111410141-151. 43. Banji D, Banji OJF, Abbagoni S, Hayath S, Kambam S, Chiluka VL: Amelioration of behavioral aberrations and oxidative markers by green tea extract in valproate induced autism in animals. Brain Res 2011;1410:141–151.

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cover image Journal of Medicinal Food
Journal of Medicinal Food
Volume 16Issue Number 11November 2013
Pages: 968 - 976
PubMed: 24117094

History

Published online: 15 November 2013
Published in print: November 2013
Published ahead of print: 11 October 2013
Accepted: 29 July 2013
Received: 19 March 2013

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Hee Rok Jeong
Department of Analytical Research, Pacificpharma Corporation, Anseong, Korea.
Division of Applied Life Science, Institute of Agriculture and Life Science, Gyeongsang National University, Jinju, Korea.
Yu Na Jo
Division of Applied Life Science, Institute of Agriculture and Life Science, Gyeongsang National University, Jinju, Korea.
Ji Hee Jeong
Division of Applied Life Science, Institute of Agriculture and Life Science, Gyeongsang National University, Jinju, Korea.
Hyeon Ju Kim
Division of Applied Life Science, Institute of Agriculture and Life Science, Gyeongsang National University, Jinju, Korea.
Man-Jo Kim
Department of Special Purpose Trees, Korea Forest Research Institute, Suwon, Korea.
Ho Jin Heo
Division of Applied Life Science, Institute of Agriculture and Life Science, Gyeongsang National University, Jinju, Korea.

Notes

Address correspondence to: Ho Jin Heo, PhD, Division of Applied Life Science, Institute of Agriculture and Life Science, Gyeongsang National University, Jinju 660-701, Korea, E-mail: [email protected]

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No competing financial interests exist.

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