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Effects of a Standardized Phenolic-Enriched Maple Syrup Extract on β-Amyloid Aggregation, Neuroinflammation in Microglial and Neuronal Cells, and β-Amyloid Induced Neurotoxicity in Caenorhabditis elegans

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Abstract

Published data supports the neuroprotective effects of several phenolic-containing natural products, including certain fruit, berries, spices, nuts, green tea, and olive oil. However, limited data are available for phenolic-containing plant-derived natural sweeteners including maple syrup. Herein, we investigated the neuroprotective effects of a chemically standardized phenolic-enriched maple syrup extract (MSX) using a combination of biophysical, in vitro, and in vivo studies. Based on biophysical data (Thioflavin T assay, transmission electron microscopy, circular dichroism, dynamic light scattering, and zeta potential), MSX reduced amyloid β1−42 peptide (Aβ1−42) fibrillation in a concentration-dependent manner (50–500 μg/mL) with similar effects as the neuroprotective polyphenol, resveratrol, at its highest test concentration (63.5 % at 500 μg/mL vs. 77.3 % at 50 μg/mL, respectively). MSX (100 μg/mL) decreased H2O2-induced oxidative stress (16.1 % decrease in ROS levels compared to control), and down-regulated the production of lipopolysaccharide (LPS)-stimulated inflammatory markers (22.1, 19.9, 74.8, and 87.6 % decrease in NOS, IL-6, PGE2, and TNFα levels, respectively, compared to control) in murine BV-2 microglial cells. Moreover, in a non-contact co-culture cell model, differentiated human SH-SY5Y neuronal cells were exposed to conditioned media from BV-2 cells treated with MSX (100 μg/mL) and LPS or LPS alone. MSX-BV-2 media increased SH-SY5Y cell viability by 13.8 % compared to media collected from LPS-BV-2 treated cells. Also, MSX (10 μg/mL) showed protective effects against Aβ1−42 induced neurotoxicity and paralysis in Caenorhabditis elegans in vivo. These data support the potential neuroprotective effects of MSX warranting further studies on this natural product.

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Abbreviations

AD:

Alzheimer’s disease

Aβ:

Amyloid-beta

MSX:

Phenolic-enriched maple syrup extract

ThT:

Thioflavin T

TEM:

Transmission electron microscopy

CD:

Circular dichroism

DLS:

Dynamic light scattering

Aβ1−42 :

Amyloid peptide 1–42

DCFDA:

2′,7′-Dichlorofluorescin diacetate

LPS:

Lipopolysaccharide

RESV:

Resveratrol

DMEM/F12:

Dulbecco’s modified Eagle medium:nutrient mixture F-12

FBS:

Fetal bovine serum

DMSO:

Dimethyl sulfoxide

MTT:

[3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]

CTG:

CellTiter-Glo

ROS:

Reactive oxygen species

NOS:

Nitric oxide species

NO:

Nitric oxide

IL-6:

Interleukin-6

PGE2 :

Prostaglandin E2

TNFα:

Tumor necrosis factorα

ELISA:

Enzyme linked immunosorbent assay

HPLC-DAD:

High performance liquid chromatography-diode array detection

GAEs:

Gallic acid equivalents

References

  1. Praticò D, Trojanowski JQ (2000) Inflammatory hypotheses: novel mechanisms of Alzheimer’s neurodegeneration and new therapeutic targets? Neurobiol Aging 21:441–445

    Article  PubMed  Google Scholar 

  2. Block ML, Zecca L, Hong J-S (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69

    Article  CAS  PubMed  Google Scholar 

  3. Heneka MT, O’Banion MK (2007) Inflammatory processes in Alzheimer’s disease. J Neuroimmunol 184:69–91

    Article  CAS  PubMed  Google Scholar 

  4. Alzheimer’s Association (2013) 2013 Alzheimer’s disease facts and figures. Alzheimers Dement 9:208–245

    Article  Google Scholar 

  5. Sloane PD, Zimmerman S, Suchindran C, Reed P, Wang L, Boustani M, Sudha S (2002) The public health impact of Alzheimer’s disease, 2000–2050: potential implication of treatment advances. Annu Rev Public Health 23:213–231

    Article  PubMed  Google Scholar 

  6. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185

    Article  CAS  PubMed  Google Scholar 

  7. Haass C, Selkoe DJ (1993) Cellular processing of β-amyloid precursor protein and the genesis of amyloid β-peptide. Cell 75:1039–1042

    Article  CAS  PubMed  Google Scholar 

  8. Herrmann N, Chau SA, Kircanski I, Lanctôt KL (2011) Current and emerging drug treatment options for Alzheimer’s disease. Drugs 71:2031–2065

    Article  CAS  PubMed  Google Scholar 

  9. Vellas B, Pesce A, Robert PH, Aisen PS, Ancoli-Israel S, Andrieu S, Cedarbaum J, Dubois B, Siemers E, Spire J-P (2011) AMPA workshop on challenges faced by investigators conducting Alzheimer’s disease clinical trials. Alzheimers Dement 7:e109–e117

    Article  PubMed  Google Scholar 

  10. Kim J, Lee HJ, Lee KW (2010) Naturally occurring phytochemicals for the prevention of Alzheimer’s disease. J Neurochem 112:1415–1430

    Article  CAS  PubMed  Google Scholar 

  11. Willis LM, Shukitt-Hale B, Joseph JA (2009) Recent advances in berry supplementation and age-related cognitive decline. Curr Opin Clin Nutr Metab Care 12:91–94

    Article  CAS  PubMed  Google Scholar 

  12. Ringman JM, Frautschy SA, Cole GM, Masterman DL, Cummings JL (2005) A potential role of the curry spice curcumin in Alzheimer’s disease. Curr Alzheimer Res 2:131–136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Abuznait AH, Qosa H, Busnena BA, El Sayed KA, Kaddoumi A (2013) Olive-oil-derived oleocanthal enhances β-amyloid clearance as a potential neuroprotective mechanism against Alzheimer’s disease: in vitro and in vivo studies. ACS Cheml Neurosci 4:973–982

    Article  CAS  Google Scholar 

  14. Wang J, Ho L, Zhao W, Ono K, Rosensweig C, Chen L, Humala N, Teplow DB, Pasinetti GM (2008) Grape-derived polyphenolics prevent Aβ oligomerization and attenuate cognitive deterioration in a mouse model of Alzheimer’s disease. J Neurosci 28:6388–6392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu RH (2013) Dietary bioactive compounds and their health implications. J Food Sci 78(Suppl 1):A18–A25

    Article  CAS  PubMed  Google Scholar 

  16. Ball DW (2007) The chemical composition of maple syrup. J Chem Edu 84:1647–1650

    Article  CAS  Google Scholar 

  17. Abou-Zaid MM, Nozzolillo C, Tonon A, Coppens M, Lombardo DA (2008) High-performance liquid chromatography characterization and identification of antioxidant polyphenols in maple syrup. Pharm Biol 46:117–125

    Article  CAS  Google Scholar 

  18. Li L, Seeram NP (2010) Maple syrup phytochemicals include lignans, coumarins, a stilbene, and other previously unreported antioxidant phenolic compounds. J Agric Food Chem 58:11673–11679

    Article  CAS  PubMed  Google Scholar 

  19. Li L, Seeram NP (2011) Further investigation into maple syrup yields 3 new lignans, a new phenylpropanoid, and 26 other phytochemicals. J Agric Food Chem 59:7708–7716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hawco CL, Wang Y, Taylor M, Weaver DF (2016) A Maple Syrup extract prevents β-amyloid aggregation. Can J Neurol Sci 43(1):198–201

    Article  PubMed  Google Scholar 

  21. Aaron C, Beaudry G, Parker JA, Therrien M (2016) Maple syrup decreases TDP-43 proteotoxicity in a Caenorhabditis elegans model of amyotrophic lateral sclerosis (ALS). J Agric Food Chem 64:3338–3344

    Article  CAS  PubMed  Google Scholar 

  22. Zhang Y, Yuan T, Li L, Nahar P, Slitt A, Seeram NP (2014) Chemical compositional, biological, and safety studies of a novel maple syrup derived extract for nutraceutical applications. J Agric Food Chem 62:6687–6698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nahar PP, Driscoll MV, Li L, Slitt AL, Seeram NP (2014) Phenolic mediated anti-inflammatory properties of a maple syrup extract in RAW 264.7 murine macrophages. J Funct Foods 6:126–136

    Article  CAS  Google Scholar 

  24. Yuan T, Ma H, Liu W, Niesen DB, Shah N, Crews R, Rose KN, Vattem DA, Seeram NP (2016) Pomegranate’s neuroprotective effects against Alzheimer’s disease are mediated by urolithins, iIts ellagitannin-gut microbial derived metabolites. ACS Chem Neurosci 7:26–33

    Article  CAS  PubMed  Google Scholar 

  25. Das S, Stark L, Musgrave IF, Pukala T, Smid SD (2016) Bioactive polyphenol interactions with β amyloid: a comparison of binding modelling, effects on fibril and aggregate formation and neuroprotective capacity. Food Funct 7:1138–1146

    Article  CAS  PubMed  Google Scholar 

  26. Shoval H, Weiner L, Gazit E, Levy M, Pinchuk I, Lichtenberg D (2008) Polyphenol-induced dissociation of various amyloid fibrils results in a methionine-independent formation of ROS. Biochim Biophys Acta 1784:1570–1577

    Article  CAS  PubMed  Google Scholar 

  27. Vetri V, Canale C, Relini A, Librizzi F, Militello V, Gliozzi A, Leone M (2007) Amyloid fibrils formation and amorphous aggregation in concanavalin A. Biophys Chem 125:184–190

    Article  CAS  PubMed  Google Scholar 

  28. Song X, Wei Z, Shaikh ZA (2015) Requirement of ERα and basal activities of EGFR and Src kinase in Cd-induced activation of MAPK/ERK pathway in human breast cancer MCF-7 cells. Toxicol Appl Pharmacol 287:26–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dowling P, Clynes M (2011) Conditioned media from cell lines: a complementary model to clinical specimens for the discovery of disease-specific biomarkers. Proteomics 11:794–804

    Article  CAS  PubMed  Google Scholar 

  30. Wang S, Wang H, Guo H, Kang L, Gao X, Hu L (2011) Neuroprotection of Scutellarin is mediated by inhibition of microglial inflammatory activation. Neuroscience 185:150–160

    Article  CAS  PubMed  Google Scholar 

  31. Liu R-P, Zou M, Wang J-Y, Zhu J-J, Lai J-M, Zhou L-L, Chen S-F, Zhang X, Zhu J-H (2014) Paroxetine ameliorates lipopolysaccharide-induced microglia activation via differential regulation of MAPK signaling. J Neuroinflamm 11:47

    Article  Google Scholar 

  32. Feng Y, Wang X-P, Yang S-G, Wang Y-J, Zhang X, Du X-T, Sun X-X, Zhao M, Huang L, Liu R-T (2009) Resveratrol inhibits beta-amyloid oligomeric cytotoxicity but does not prevent oligomer formation. Neurotoxicology 30:986–995

    Article  CAS  PubMed  Google Scholar 

  33. Dai X, Hou W, Sun Y, Gao Z, Zhu S, Jiang Z (2015) Chitosan oligosaccharides inhibit/disaggregate fibrils and attenuate amyloid β-mediated neurotoxicity. Int J Mol Sci 16:10526–10536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhong L-M, Zong Y, Sun L, Guo J-Z, Zhang W, He Y, Song R, Wang W-M, Xiao C-J, Lu D (2012) Resveratrol inhibits inflammatory responses via the mammalian target of rapamycin signaling pathway in cultured LPS-stimulated microglial cells. PloS One 7:e32195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shih Y-T, Chen I-J, Wu Y-C, Lo Y-C (2011) San-Huang-Xie-Xin-Tang protects against activated microglia- and 6-OHDA-induced toxicity in neuronal SH-SY5Y cells. Evid Based Complement Alternat Med 2011:429384

    PubMed  PubMed Central  Google Scholar 

  36. Cohen E, Dillin A (2008) The insulin paradox: aging, proteotoxicity and neurodegeneration. Nat Rev Neurosci 9:759–767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Radak Z, Zhao Z, Goto S, Koltai E (2011) Age-associated neurodegeneration and oxidative damage to lipids, proteins and DNA. Mol Aspects Med 32:305–315

    Article  CAS  PubMed  Google Scholar 

  38. Shukla V, Mishra SK, Pant HC (2011) Oxidative stress in neurodegeneration. Adv Pharmacol Sci 1043:545–552

    Google Scholar 

  39. de Fátima Bezerra M, Jamison BY, Gomada Y, Borges KC, Correia RTP, Vattem DA (2014) Eugenia jambolana Lam. Increases lifespan and ameliorates experimentally induced neurodegeneration in C. elegans. Int J Appl Res Nat Prod 7:39–48

    Google Scholar 

  40. Azevêdo JC, Borges KC, Genovese MI, Correia RT, Vattem DA (2015) Neuroprotective effects of dried camu-camu (Myrciaria dubia HBK McVaugh) residue in C. elegans. Food Res Int 73:135–141

    Article  Google Scholar 

  41. Wu Y, Wu Z, Butko P, Christen Y, Lambert MP, Klein WL, Link CD, Luo Y (2006) Amyloid-β-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J Neurosci 26:13102–13113

    Article  CAS  PubMed  Google Scholar 

  42. Dostal V, Roberts CM, Link CD (2010) Genetic mechanisms of coffee extract protection in a Caenorhabditis elegans model of β-amyloid peptide toxicity. Genetics 186:857–866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The spectroscopic data were acquired from instruments located in the RI-INBRE core facility supported by Grant # P20GM103430 from the National Institute of General Medical Sciences of the National Institutes of Health. We thank Dr. Grace Y. Sun (University of Missouri at Columbia, MO, USA) for kindly providing the BV-2 murine microglial cells and Dr. Richard Kingsley and the URI TEM facility (URI Chemical Engineering) for assisting with TEM sample imaging.

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Author notes

  1. Dhiraj A. Vattem

    Present address: School of Applied Health Sciences and Wellness, Grover Center E160A, Ohio University, Athens, OH, 45701, USA

Authors and Affiliations

  1. Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, 02881, USA

    Hang Ma, Nicholas A. DaSilva, Weixi Liu, Pragati P. Nahar, Zhengxi Wei, Yongqiang Liu, Angela L. Slitt, Zahir A. Shaikh & Navindra P. Seeram

  2. Nutrition Biomedicine and Biotechnology, Texas State University, San Marcos, TX, 78666, USA

    Priscilla T. Pham, Rebecca Crews & Dhiraj A. Vattem

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  1. Hang Ma
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Ma, H., DaSilva, N.A., Liu, W. et al. Effects of a Standardized Phenolic-Enriched Maple Syrup Extract on β-Amyloid Aggregation, Neuroinflammation in Microglial and Neuronal Cells, and β-Amyloid Induced Neurotoxicity in Caenorhabditis elegans . Neurochem Res 41, 2836–2847 (2016). https://doi.org/10.1007/s11064-016-1998-6

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