PDF herunterladen
Planta Med 2015; 81(05): 357-362
DOI: 10.1055/s-0035-1545724
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Extracts of Glycyrrhiza uralensis and Isoliquiritigenin Counteract Amyloid-β Toxicity in Caenorhabditis elegans

Pille Link
1   Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany
,
Bernhard Wetterauer
1   Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany
,
Yujie Fu
2   Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin, China
,
Michael Wink
1   Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 04. November 2014
revised 26. Januar 2015

accepted 29. Januar 2015

Publikationsdatum:
17. März 2015 (online)

Auch verfügbar auf
   Lizenzen und Reprints

Abstract

Alzheimerʼs disease is a rising threat for modern societies as more and more people reach old age. To date, there is no effective treatment for this condition. In this study, we investigated the potential of Glycyrrhiza uralensis to counteract amyloid-β toxicity, one of the key features of Alzheimerʼs disease. An LC-MS/MS analysis revealed glycyrrhizic acid and glycosylated forms of isoliquiritigenin and liquiritigenin as major constituents of water and methanol extracts of G. uralensis. These extracts and the pure compounds were tested for their activity in two Caenorhabditis elegans models of amyloid-β aggregation and amyloid-β toxicity, respectively. The number of amyloid-β aggregates decreased by 30 % after treatment with isoliquiritigenin, the methanol extract could reduce the number by 14 %, liquiritigenin and glycyrrhizic acid by 15 %, and the aglycon of glycyrrhizic acid, glycyrrhetinic acid, by 20 %. Both extracts and isoliquiritigenin also showed significant activity against acute amyloid-β toxicity in transgenic C. elegans that express human amyloid-β peptides, delaying the paralysis in this model by 1.8 h and 1.1 h, respectively. We conclude that secondary compounds of G. uralensis may become interesting drug candidates for the treatment of Alzheimerʼs disease, which, however, need further analysis in other model systems.

Key words

Glycyrrhiza uralensis - Fabaceae - LC-MS/MS analysis - isoliquiritigenin - amyloid-β - Caenorhabditis elegans
 

  • References

  • 1 Prince M, Jackson J editors. World Alzheimer Report. London: Alzheimerʼs Disease International; 2009
    Suche in Google Scholar
  • 2 Wink M. Evolution of secondary metabolites from an ecological and molecular phylogenetic perspective. Phytochemistry 2003; 64: 3-19
    CrossrefPubMedSuche in Google Scholar
  • 3 Asl MN, Hosseinzadeh H. Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. Phytother Res 2008; 22: 709-724
    CrossrefPubMedSuche in Google Scholar
  • 4 Guo J, Shang E, Zhao J, Fan X, Duan J, Qian D, Tao W, Tang Y. Data mining and frequency analysis for licorice as a “Two-Face” herb in Chinese Formulae based on Chinese Formulae Database. Phytomedicine 2014; 21: 1281-1286
    CrossrefPubMedSuche in Google Scholar
  • 5 Dhingra D, Parle M, Kulkarni SK. Memory enhancing activity of Glycyrrhiza glabra in mice. J Ethnopharmacol 2004; 91: 361-365
    CrossrefPubMedSuche in Google Scholar
  • 6 Kanno H, Kawakami Z, Iizuka S, Tabuchi M, Mizoguchi K, Ikarashi Y, Kase Y. Glycyrrhiza and Uncaria Hook contribute to protective effect of traditional Japanese medicine yokukansan against amyloid beta oligomer-induced neuronal death. J Ethnopharmacol 2013; 149: 360-370
    CrossrefPubMedSuche in Google Scholar
  • 7 Ahn J, Um M, Choi W, Kim S, Ha T. Protective effects of Glycyrrhiza uralensis Fisch. on the cognitive deficits caused by beta-amyloid peptide 25–35 in young mice. Biogerontology 2006; 7: 239-247
    CrossrefPubMedSuche in Google Scholar
  • 8 Wang CY, Kao TC, Lo WH, Yen GC. Glycyrrhizic acid and 18beta-glycyrrhetinic acid modulate lipopolysaccharide-induced inflammatory response by suppression of NF-kappaB through PI3K p 110delta and p 110gamma inhibitions. J Agric Food Chem 2011; 59: 7726-7733
    CrossrefPubMedSuche in Google Scholar
  • 9 Luo L, Jin Y, Kim ID, Lee JK. Glycyrrhizin attenuates kainic acid-induced neuronal cell death in the mouse hippocampus. Exp Neurobiol 2013; 22: 107-115
    CrossrefPubMedSuche in Google Scholar
  • 10 Kim JY, Park SJ, Yun KJ, Cho YW, Park HJ, Lee KT. Isoliquiritigenin isolated from the roots of Glycyrrhiza uralensis inhibits LPS-induced iNOS and COX-2 expression via the attenuation of NF-kappaB in RAW 264.7 macrophages. Eur J Pharmacol 2008; 584: 175-184
    CrossrefPubMedSuche in Google Scholar
  • 11 Takahashi T, Takasuka N, Iigo M, Baba M, Nishino H, Tsuda H, Okuyama T. Isoliquiritigenin, a flavonoid from licorice, reduces prostaglandin E2 and nitric oxide, causes apoptosis, and suppresses aberrant crypt foci development. Cancer Sci 2004; 95: 448-453
    CrossrefPubMedSuche in Google Scholar
  • 12 Park SJ, Youn HS. Suppression of homodimerization of toll-like receptor 4 by isoliquiritigenin. Phytochemistry 2010; 71: 1736-1740
    CrossrefPubMedSuche in Google Scholar
  • 13 Hwang CK, Chun HS. Isoliquiritigenin isolated from licorice Glycyrrhiza uralensis prevents 6-hydroxydopamine-induced apoptosis in dopaminergic neurons. Biosci Biotechnol Biochem 2012; 76: 536-543
    CrossrefPubMedSuche in Google Scholar
  • 14 Yang EJ, Min JS, Ku HY, Choi HS, Park MK, Kim MK, Song KS, Lee DS. Isoliquiritigenin isolated from Glycyrrhiza uralensis protects neuronal cells against glutamate-induced mitochondrial dysfunction. Biochem Biophys Res Commun 2012; 421: 658-664
    CrossrefPubMedSuche in Google Scholar
  • 15 Kawakami Z, Ikarashi Y, Kase Y. Isoliquiritigenin is a novel NMDA receptor antagonist in kampo medicine yokukansan. Cell Mol Neurobiol 2011; 31: 1203-1212
    CrossrefPubMedSuche in Google Scholar
  • 16 Wang W, Hu X, Zhao Z, Liu P, Hu Y, Zhou J, Zhou D, Wang Z, Guo D, Guo H. Antidepressant-like effects of liquiritin and isoliquiritin from Glycyrrhiza uralensis in the forced swimming test and tail suspension test in mice. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 1179-1184
    CrossrefPubMedSuche in Google Scholar
  • 17 Liu RT, Zou LB, Lu QJ. Liquiritigenin inhibits Abeta(25–35)-induced neurotoxicity and secretion of Abeta(1–40) in rat hippocampal neurons. Acta Pharmacol Sin 2009; 30: 899-906
    CrossrefPubMedSuche in Google Scholar
  • 18 Lee HK, Yang EJ, Kim JY, Song KS, Seong YH. Inhibitory effects of glycyrrhizae radix and its active component, isoliquiritigenin, on Abeta(25–35)-induced neurotoxicity in cultured rat cortical neurons. Arch Pharm Res 2012; 35: 897-904
    CrossrefPubMedSuche in Google Scholar
  • 19 Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimerʼs disease: progress and problems on the road to therapeutics. Science 2002; 297: 353-356
    CrossrefPubMedSuche in Google Scholar
  • 20 Walsh DM, Selkoe DJ. A beta oligomers – a decade of discovery. J Neurochem 2007; 101: 1172-1184
    CrossrefPubMedSuche in Google Scholar
  • 21 Link CD. C. elegans models of age-associated neurodegenerative diseases: lessons from transgenic worm models of Alzheimerʼs disease. Exp Gerontol 2006; 41: 1007-1013
    CrossrefPubMedSuche in Google Scholar
  • 22 Montoro P, Maldini M, Russo M, Postorino S, Piacente S, Pizza C. Metabolic profiling of roots of liquorice (Glycyrrhiza glabra) from different geographical areas by ESI/MS/MS and determination of major metabolites by LC-ESI/MS and LC-ESI/MS/MS. J Pharm Biomed Anal 2011; 54: 535-544
    CrossrefPubMedSuche in Google Scholar
  • 23 Farag MA, Porzel A, Wessjohann LA. Comparative metabolite profiling and fingerprinting of medicinal licorice roots using a multiplex approach of GC–MS, LC–MS and 1D NMR techniques. Phytochemistry 2012; 76: 60-72
    CrossrefPubMedSuche in Google Scholar
  • 24 Lee YS, Kim SH, Kim JK, Shin HK, Kang YH, Park JH, Lim SS. Rapid identification and preparative isolation of antioxidant components in licorice. J Sep Sci 2010; 33: 664-671
    CrossrefPubMedSuche in Google Scholar
  • 25 Drake J, Link CD, Butterfield DA. Oxidative stress precedes fibrillar deposition of Alzheimerʼs disease amyloid beta-peptide (1–42) in a transgenic Caenorhabditis elegans model. Neurobiol Aging 2003; 24: 415-420
    CrossrefPubMedSuche in Google Scholar
  • 26 Cohen E, Bieschke J, Perciavalle RM, Kelly JW, Dillin A. Opposing activities protect against age-onset proteotoxicity. Science 2006; 313: 1604-1610
    CrossrefPubMedSuche in Google Scholar
  • 27 Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ. Decreased clearance of CNS beta-amyloid in Alzheimerʼs disease. Science 2010; 330: 1774
    CrossrefPubMedSuche in Google Scholar
  • 28 Liu RT, Tang JT, Zou LB, Fu JY, Lu QJ. Liquiritigenin attenuates the learning and memory deficits in an amyloid protein precursor transgenic mouse model and the underlying mechanisms. Eur J Pharmacol 2011; 669: 76-83
    CrossrefPubMedSuche in Google Scholar
  • 29 Vaya J, Belinky PA, Aviram M. Antioxidant constituents from licorice roots: isolation, structure elucidation and antioxidative capacity toward LDL oxidation. Free Radic Biol Med 1997; 23: 302-313
    CrossrefPubMedSuche in Google Scholar
  • 30 Zhang X, Zhu P, Zhang X, Ma Y, Li W, Chen JM, Guo HM, Bucala R, Zhuang J, Li J. Natural antioxidant-isoliquiritigenin ameliorates contractile dysfunction of hypoxic cardiomyocytes via AMPK signaling pathway. Mediators Inflamm 2013; 2013: 390890
    PubMedSuche in Google Scholar
  • 31 Chen YP, Zhang ZY, Li YP, Li D, Huang SL, Gu LQ, Xu J, Huang ZS. Syntheses and evaluation of novel isoliquiritigenin derivatives as potential dual inhibitors for amyloid-beta aggregation and 5-lipoxygenase. Eur J Med Chem 2013; 66: 22-31
    CrossrefPubMedSuche in Google Scholar
  • 32 Han SY, Chin YW, Choi YH. A new approach for pharmacokinetic studies of natural products: measurement of isoliquiritigenin levels in mice plasma, urine and feces using modified automated dosing/blood sampling system. Biomed Chromatogr 2013; 27: 741-749
    Suche in Google Scholar
  • 33 Qiao H, Zhang X, Wang T, Liang L, Chang W, Xia H. Pharmacokinetics, biodistribution and bioavailability of isoliquiritigenin after intravenous and oral administration. Pharm Biol 2014; 52: 228-236
    CrossrefPubMedSuche in Google Scholar
  • 34 Zheng SQ, Ding AJ, Li GP, Wu GS, Luo HR. Drug absorption efficiency in Caenorhabditis elegans delivered by different methods. PLoS One 2013; 8: e56877
    CrossrefPubMedSuche in Google Scholar
  • 35 Zeng L, Zhang RY, Meng T, Lou ZC. Determinatin of nine flavonoids and coumarins in licorice root by high-performance liquid chromatography. J Chromatogr A 1990; 513: 247-254
    CrossrefPubMedSuche in Google Scholar
  • 36 Link CD. Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans . Proc Natl Acad Sci U S A 1995; 92: 9368-9372
    CrossrefPubMedSuche in Google Scholar
  • 37 Sulston J, Hodgkin J. Methods. In: Wood WB, editor The nematode Caenorhabditis elegans . Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press; 1988: 587-606
    Suche in Google Scholar
  • 38 Fay DS, Fluet A, Johnson CJ, Link CD. In vivo aggregation of β-amyloid peptide variants. J Neurochem 1998; 71: 1616-1625
    PubMedSuche in Google Scholar
  • 39 Abbas S, Wink M. Epigallocatechin gallate inhibits beta amyloid oligomerization in Caenorhabditis elegans and affects the daf-2/insulin-like signaling pathway. Phytomedicine 2010; 17: 902-909
    CrossrefPubMedSuche in Google Scholar
  • 40 Dostal V, Link CD. Assaying beta-amyloid toxicity using a transgenic C. elegans model. J Vis Exp 2010; 44: 11-16
    PubMedSuche in Google Scholar