Food Science and Biotechnology

  • 제17권6호
  • /
  • Pages.1165-1170
  • /
  • 2008
  • /
  • 1226-7708(pISSN)
  • /
  • 2092-6456(eISSN)
한국식품과학회 (Korean Society of Food Science and Technology)
권호 표지

Inhibitory Effects of Flavonoids Isolated from Leaves of Petasites japonicus on $\beta$-Secretase (BACE1)

  • Song, Kyung-Sik (Division of Applied Biology and Chemistry, College of Agriculture and Life Sciences, Kyungpook National University) ;
  • Choi, Sun-Ha (Division of Applied Biology and Chemistry, College of Agriculture and Life Sciences, Kyungpook National University) ;
  • Hur, Jong-Moon (Division of Applied Biology and Chemistry, College of Agriculture and Life Sciences, Kyungpook National University) ;
  • Park, Hyo-Jun (Division of Applied Biology and Chemistry, College of Agriculture and Life Sciences, Kyungpook National University) ;
  • Yang, Eun-Ju (Division of Applied Biology and Chemistry, College of Agriculture and Life Sciences, Kyungpook National University) ;
  • MookJung, In-Hee (Department of Biochemistry, College of Medicine, Seoul National University) ;
  • Yi, Jung-Hyun (Division of Food Science, Dong-A University) ;
  • Jun, Mi-Ra (Division of Food Science, Dong-A University)
  • 발행 : 2008.12.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

The deposition of the amyloid $\beta}$ ($A{\beta}$)-peptide following proteolytic processing of amyloid precursor protein (APP) by $\beta$-secretase (BACE1) and $\gamma$-secretase is critical feature in the progress of Alzheimer's disease (AD). Consequently, BACE1, a key enzyme in the production of $A{\beta}$, is a prime target for therapeutic intervention in AD. In the course of searching for BACE1 inhibitors from natural sources, the ethyl acetate fraction of Petasites japonicus showed potent inhibitory activity. Two BACE1 inhibitors quercetin (QC) and kaempferol 3-O-(6"-acetyl)-$\beta$-glucopyranoside (KAG) were isolated from P. japonicus by activity-guided purification. QC, in particular, non-competitively attenuated BACE1 activity with $IC_{50}$ value of $2.1{\times}10^{-6}\;M$ and $K_i$ value of $3.7{\times}10^{-6}\;M$. Both compounds exhibited less inhibition of $\alpha$-secreatase (TACE) and other serine proteases including chymotrypsin, trypsin, and elastase, suggesting that they ere relatively specific and selective inhibitors to BACE1. Furthermore, both compounds significantly reduced the extracellular $A{\beta}$ secretion in $APP_{695}$-transfected B103 cells.

키워드

참고문헌

  1. Glenner GG, Wong CW. Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Bioph. Res. Co. 120: 885-890 (1984) https://doi.org/10.1016/S0006-291X(84)80190-4
  2. Citron M. Strategies for disease modification in Alzheimer's disease. Nat. Rev. Neurosci. 5: 677-685 (2004) https://doi.org/10.1038/nrn1495
  3. Jucker M, Beyreuther K, Aass C, Nitsch RM, Christein T. In Alzheimer: 100 years and Beyond. Springer, Berlin, Germany (2006)
  4. Selkoe DJ. Normal and abnormal biology of the ${\beta}-amyloid$ precursor protein. Annu. Rev. Neurosci. 17: 489-517 (1994) https://doi.org/10.1146/annurev.ne.17.030194.002421
  5. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286: 735-741 (1999) https://doi.org/10.1126/science.286.5440.735
  6. Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, Zhao J, McConlogue L, John V. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402: 537-540 (1999) https://doi.org/10.1038/990114
  7. Dewachter I, Van Leuven F. Secretases as targets for the treatment of Alzheimer's disease: The prospects. Lancet Neurol. 1: 409-416 (2002) https://doi.org/10.1016/S1474-4422(02)00188-6
  8. Debrenner B, Meier B. Petasites hybridus: A tool for interdisciplinary research in phytotheraphy. Pharm. Acta Helv. 72: 359-380 (1998) https://doi.org/10.1016/S0031-6865(97)00027-7
  9. Niwa H, Ishiwata H, Yamada K. Separation and determination of macrocyclic pyrrolizidine alkaloids of the otonecine type present in the edible plant Petasites japonicus by reversed-phase high performance liquid chromatography. J. Chromatogr. 257: 146-150 (1983) https://doi.org/10.1016/S0021-9673(01)88166-8
  10. Hirono I, Mori H, Yamada K, Hirata Y, Haga M. Carcinogenic activity of petasitenine, a new pyrrolizidine alkaloid isolated from Petasites japonicus Maxim. J. Natl. Cancer I. 58: 1155-1157 (1977) https://doi.org/10.1093/jnci/58.4.1155
  11. Furuya T, Hikichi M, Iitaka Y. Fukinotoxin, a new pyrrolizidine alkaloid from Petasites. Chem. Pharm. Bull. 24: 1120-1122 (1976) https://doi.org/10.1248/cpb.24.1120
  12. Hasa Y, Tazaki H. Biosynthesis of fukinolic acid isolated from Petasites japonicus. Biosci. Biotech. Bioch. 68: 2212-2214 (2004) https://doi.org/10.1271/bbb.68.2212
  13. Lin C-H, Li C-Y, Wu T-S. A novel phenulpropenoyl sulfonic acid and a new chlorophyll from the leaves of Petasites formosanus Kitamura. Chem. Pharm. Bull. 52: 1151-1152 (2004) https://doi.org/10.1248/cpb.52.1151
  14. Sok D-E, Oh SH, Kim Y-B, Kang H-G, Kim M. Neuroproection by extract of Petasites japonicus leaves, a traditional vegetable, against oxidative stress in brain of mice challenged with kainic acid. Eur. J. Nutr. 45: 61-69 (2006) https://doi.org/10.1007/s00394-005-0565-8
  15. Slimestad R, Andersen QM, Francis GW, Marston A. Syringetin (3-O-(6''-acetyl)-${\beta}$-glucopyranoside and other flavonols from needles of Norway spruce. Phytochemistry 405: 1537-1542 (1995)
  16. Xu HX, Yang D, Wyss-Coray T, Yan J, Gan L, Sun Y, Mucke L. Wild type but not Alzheimer-mutant amyloid precursor protein confers resistence against p53-mediated apoptosis. P. Natl. Acad. Sci. USA 96: 7547-7552 (1999)
  17. Jeon SY, Bae K, Seong YH, Song KS. Green tea catechins as a BACE1 $({\beta}-secretase)$ inhibitors. Bioorg. Med. Chem. Lett. 13: 3905-3908 (2003) https://doi.org/10.1016/j.bmcl.2003.09.018
  18. Jun M, Lee S-H, Choi S-H, Bae K, Seong Y-H, Lee K-B, Song K-S. Plant phenolics as ${\beta}-secretase$ (BACE1) inhibitors. Food Sci. Biotechnol. 15: 617-624 (2006)
  19. Shuto D, Kasai S, Kimura T, Liu P, Hidaka K, Hamada T, Shibakawa S, Hayashi Y, Hattori C, Szabo B, Ishiura S, Kiso Y. KMI-008, a novel ${\beta}-secretase$ inhibitor containing a hydroxy-methylcarbonyl isostere as a transition-state mimic: Design and synthesis of substrate-based octapeptides. Bioorg. Med. Chem. Lett. 13: 4273-4276 (2003) https://doi.org/10.1016/j.bmcl.2003.09.053
  20. Ghosh AK, Shin D, Downs D, Koelsch G, Lin X, Ermolieff J, Tang J. Design of potent inhibitors for human brain memapsin 2 $({\beta}-secretase)$. J. Am. Chem. Soc. 122: 3522-3523 (2000) https://doi.org/10.1021/ja000300g
  21. Turner RT, Koelsch G, Hong L, Castanheira P, Ghosh AK, Tang J, Castenheira P, Ghosh A. Subsite specificity of memapsin 2 $({\beta}-secretase)$: Implications for inhibitor design. Biochemistry 40: 10001-10006 (2001) https://doi.org/10.1021/bi015546s
  22. Yang W, Lu W, Lu Y, Zhong M, Sun J, Thomas AE, Wilkinson JM, Fucini RV, Lam M, Randal M, Shi XP, Jacobs JW, McDowell RS, Gordon EM, Balliner MD. Aminoethylenes: A tetrahedral intermediate isostere yielding potent inhibitors of the aspartyl protease BACE1. J. Med. Chem. 49: 839-842 (2006) https://doi.org/10.1021/jm0509142
  23. Vassar R. ${\beta}-Secretase$ (BACE) as a drug target for Alzheimer's disease. Adv. Drug Deliver. Rev. 54: 1589-1602 (2002) https://doi.org/10.1016/S0169-409X(02)00157-6
  24. Kwak HM, Jeon SY, Sohng BH, Kim JG, Lee JM, Lee KB, Jeong HH, Hur JM, Kang YH, Song KS. ${\beta}-Secretase$ (BACE1) inhibitors from pomegranate (Punica granatum) husk. Arch. Pharm. Res. 28: 1328-1332 (2005) https://doi.org/10.1007/BF02977896
  25. Park IH, Jeon SY, Lee HJ, Kim SI, Song KS. A ${\beta}-secretase$ inhibitor hispidin from the mycelial cultures of Phellinus linteus. Planta Med. 70: 143-146 (2004) https://doi.org/10.1055/s-2004-815491
  26. Lee HJ, Seong YH, Bae KH, Kwon SH, Kwak HM, Nho SK, Kim KA, Hur JM, Lee KB, Kang YH, Song KS. ${\beta}-Secretase$ (BACE1) inhibitors from Sanguisorbae radix. Arch. Pharm. Res. 28: 799-803 (2005) https://doi.org/10.1007/BF02977345
  27. Je JY, Kim SK. Water-soluble chitosan derivatives as a BACE1 inhibitor. Bioorg. Med. Chem. Lett. 13: 6551-6555 (2005) https://doi.org/10.1016/j.bmc.2005.07.004
  28. Miranda S, Opazo C, Larrondo LF, Munoz FJ, Ruiz F, Leighton F, Inestrosa NC. The role of oxidative stress in the toxicity induced by amyloid ${beta}-peptide$ in Alzheimer's disease. Prog. Neurobiol. 62: 633-648 (2000) https://doi.org/10.1016/S0301-0082(00)00015-0
  29. Hussain I, Hawkins J, Harrison D, Hille C, Wayne G, Cutler L, Buck T, Walter D, Demont E, Howes C, Naylor A, Jeffrey P, Gonzalez MI, Dingwall C, Michel A, Redshaw S, Davis JB. Oral administration of a potent and selective non-peptidic BACE-1 inhibitor decreases beta-cleavage of amyloid precursor protein and $amyloid-{\beta}$ production in vivo. J. Neurochem. 100: 802-809 (2007) https://doi.org/10.1111/j.1471-4159.2006.04260.x
  30. Youdim KA, Zeeshan A, Qaiser M, Begley DJ, Rice-Evans CA, Abbott NJ. Flavonoid permeability across an in situ model of the blood-brain barrier. Free Radical Bio. Med. 5: 592-604 (2004)
  31. Csokay B, Parajda N, Weber G, Olah E. Molecular mechanism in the antiproliferative action of quercetin. Life Sci. 60: 2157-2163 (1997) https://doi.org/10.1016/S0024-3205(97)00230-0
  32. Eberhardt MV, Lee CY, Liu RH. Antioxidant activity of fresh apples. Nature 405: 903-904 (2000)
  33. Kim DO, LEE KW, Lee HJ, Lee CY. Vitamin C equivalent antioxidant capacity (VCEAC) of phenolic phytochemicals. J. Agr. Food Chem. 50: 3713-3717 (2002) https://doi.org/10.1021/jf020071c
  34. Heo HJ, Lee CY. Protective effects of quercetin and vitamin C against oxidative stress induced neurodegeneration. J. Agr. Food Chem. 52: 7514-7517 (2004) https://doi.org/10.1021/jf049243r
  35. Ishige K, Schubert D, Sagara Y. Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free Radical Bio. Med. 30: 433-446 (2001) https://doi.org/10.1016/S0891-5849(00)00498-6