Download PDF
Planta Med 2014; 80(12): 1001-1008
DOI: 10.1055/s-0034-1382949
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Kavalactones, A Novel Class of Protein Glycation and Lipid Peroxidation Inhibitors

Atul Upadhyay
Natural Products & Food Research and Analysis (NatuRA), Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium
,
Emmy Tuenter
Natural Products & Food Research and Analysis (NatuRA), Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium
,
Rizwan Ahmad
Natural Products & Food Research and Analysis (NatuRA), Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium
,
Adnan Amin
Natural Products & Food Research and Analysis (NatuRA), Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium
,
Vasiliki Exarchou
Natural Products & Food Research and Analysis (NatuRA), Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium
,
Sandra Apers
Natural Products & Food Research and Analysis (NatuRA), Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium
,
Nina Hermans
Natural Products & Food Research and Analysis (NatuRA), Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium
,
Luc Pieters
Natural Products & Food Research and Analysis (NatuRA), Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium
› Author Affiliations
Further Information

Publication History

received 25 May 2014

accepted 07 July 2014

Publication Date:
06 August 2014 (online)

Also available at
    Permissions and Reprints

Abstract

Both advanced glycation endproducts and advanced lipoxidation endproducts are implicated in many age-related chronic diseases and in protein ageing. In this study, kawain, methysticin, and dihydromethysticin, all belonging to the group of kavalactones, were identified as advanced glycation endproduct inhibitors. With IC50 values of 43.5 ± 1.2 µM and 45.0 ± 1.3 µM for kawain and methysticin, respectively, the compounds inhibited the in vitro protein glycation significantly better than aminoguanidine (IC50 = 231.0 ± 11.5 µM; p = 0.01), an established reference compound. Kawain and methysticin also inhibited the formation of dicarbonyl compounds, which are intermediates in the process of advanced glycation endproduct formation. Similarly, kawain and aminoguanidine prevented the formation of thiobarbituric reactive substances in both low-density lipoprotein and linoleic acid oxidation. Moreover, kawain and aminoguanidine prevented advanced glycation endproduct formation by chelating Fe3+ and Cu2+ two to three times better than aminoguanidine. Furthermore, kawain increased the mean life span of Caenorhabditis elegans exposed to high glucose. With glycation inhibiting, lipid peroxidation inhibiting, metal chelating properties, and life span extending ability, kavalactones show a high potential as advanced glycation endproducts and advanced lipoxidation endproduct inhibitors.

Key words

advanced glycation endproducts (AGEs) - advanced lipoxidation endproducts (ALEs) kavalactones - kawain - chelation - Caenorhabditis elegans
 

  • References

  • 1 Schmidt AM, Hori O, Brett J, Yan SD, Wautier JL, Stern D. Cellular receptors for advanced glycation endproducts. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Arterioscler Thromb 1994; 14: 1521-1528
    CrossrefPubMedSearch in Google Scholar
  • 2 Munch G, Thome J, Foley P, Schinze R, Riederer P. Advanced glycation endproducts in ageing and Alzheimerʼs disease. Brain Res Rev 1997; 23: 134-143
    CrossrefPubMedSearch in Google Scholar
  • 3 Baynes JW. Pyridoxamie, a versatile inhibitor of advanced glycation and lipoxidation reactions. Int Congr Ser 2002; 1245: 31-35
    CrossrefPubMedSearch in Google Scholar
  • 4 Basta G, Schmidt AM, Caterina RD. Avanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res 2004; 63: 582-592
    CrossrefPubMedSearch in Google Scholar
  • 5 Heijst JWJV, Niessen HWM, Hoekman K, Schalkwijk CG. Advanced glycation end products in human cancer tissues. Ann N Y Acad Sci 2006; 1043: 725-733
    PubMedSearch in Google Scholar
  • 6 Negre-Salvayre A, Auge N, Ayala V, Basaga H, Boada J, Brenke R, Chapple S, Cohen G, Feher J, Grune T, Lengyel G, Mann GE, Pamplona R, Poli G, Portero-Otin M, Riahi Y, Salvayre R, Sasson S, Serrano J, Shamni O, Siems W, Siow RCM, Wiswedel I, Zarkovic K, Zarkovic N. Pathological aspects of lipid peroxidation. Free Radic Res 2010; 44: 1125-1171
    CrossrefPubMedSearch in Google Scholar
  • 7 Boerner RJ, Sommer H, Berger W, Kuhn U, Schmidt U, Mannel M. Kava-kava extract LI 150 is as effective as opipramol and buspirone in generalised anxiety disorder – an 8-week randomized, double-blind multi-centre clinical trial in 129 out-patients. Phytomedicine 2003; 10 Suppl. 4: 38-49
    CrossrefPubMedSearch in Google Scholar
  • 8 Upadhyay A, Chompoo J, Kishimoto W, Makise T, Tawata S. HIV-1 integrase and neuraminidase inhibitors from Alpinia zerumbet . J Agric Food Chem 2011; 59: 2857-2862
    CrossrefPubMedSearch in Google Scholar
  • 9 Xuan TD, Fukuta M, Wei AC, Elzaawely AA, Khanh TD, Tawata S. Efficacy of extracting solvents to chemical components of kava (Piper methysticum) roots. J Nat Med 2008; 62: 188-194
    CrossrefPubMedSearch in Google Scholar
  • 10 Chompoo J, Upadhyay A, Kishimoto W, Makise T, Tawata S. Advanced glycation end products inhibitors from Alpinia zerumbet rhizomes. Food Chem 2011; 129: 709-715
    CrossrefPubMedSearch in Google Scholar
  • 11 Hidalgo FJ, Zamora R. Interplay between the maillard reaction and lipid peroxidation in biochemical systems. Ann N Y Acad Sci 2005; 1043: 319-326
    CrossrefPubMedSearch in Google Scholar
  • 12 Rahbar S. Novel inhibitors of glycation and AGE formation. Cell Biochem Biophys 2007; 48: 147-157
    CrossrefPubMedSearch in Google Scholar
  • 13 Harris CS, Beaulieu LP, Fraser MH, McIntyre KL, Owen PL, Martineau LC, Cuerrier A, Johns T, Haddad PS, Bennett AL, Arnason JT. Inhibition of advanced glycation end product formation by medicinal plant extracts correlated with phenolic metabolites and antioxidant activity. Planta Med 2011; 77: 196-204
    Thieme ConnectPubMedSearch in Google Scholar
  • 14 Pashikanti S, De Alba DR, Boissonneault GA, Cervantes-Laurean D. Rutin metabolites: novel inhibitors of nonoxidative advanced glycation end products. Free Rad Biol Med 2010; 48: 656-663
    CrossrefPubMedSearch in Google Scholar
  • 15 Morel S, Helesbeux JJ, Séraphin D, Derbré S, Gatto J, Aumond MC, Abatuci Y, Grellier P, Beniddir MA, Le Pape P, Pagniez F, Litaudon M, Landreau A, Richomme P. Anti-AGEs and antiparasitic activity of an original prenylated isoflavonoid and flavanones isolated from Derris ferruginea . Phytochemistry Lett 2013; 6: 498-503
    CrossrefPubMedSearch in Google Scholar
  • 16 Rahbar S, Natarajan R, Yerneni KK, Scott S, Gonzales N, Nadler JL. Evidence that pioglitazone, metformin and pentoxifylline are inhibitors of glycation. Clin Chim Acta 2000; 301: 65-77
    CrossrefPubMedSearch in Google Scholar
  • 17 Brownlee M. Biochemistry and molecular biology of diabetic complications. Nature 2001; 414: 813-820
    CrossrefPubMedSearch in Google Scholar
  • 18 Voziyan PA, Metz TO, Baynes JW, Hudso BG. A post-Amadori inhibitor pyridoxamine also inhibits chemical modification of proteins by scavenging carbonyl intermediates of carbohydrate and lipid degradation. J Biol Chem 2002; 277: 3397-3403
    CrossrefPubMedSearch in Google Scholar
  • 19 Nagai R, Murray DB, Metz TO, Baynes JW. Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications. Diabetes 2012; 61: 549-559
    CrossrefPubMedSearch in Google Scholar
  • 20 Price DL, Rhett PM, Thorpe SR, Baynes JW. Chelating activity of advanced glycation end-product inhibitors. J Biol Chem 2001; 276: 48967-48972
    CrossrefPubMedSearch in Google Scholar
  • 21 Sajithlal GB, Chithra P, Chandrakasan G. The role of metal catalysed oxidation in the formation of advanced glycation end products: an in vitro study on collagen. Free Rad Biol Med 1998; 25: 265-269
    CrossrefPubMedSearch in Google Scholar
  • 22 Onorato JM, Jenkins AJ, Thorpe SR, Baynes JW. Pyridoxamine, an inhibitor of advanced glycation reactions, also inhibits advanced lipoxidation reactions. J Biol Chem 2000; 275: 21177-21184
    CrossrefPubMedSearch in Google Scholar
  • 23 Miyata T, Ueda Y, Asahi K, Izuhara Y, Inagi R, Saito A, van Ypersele de Strihou C, Kurokawa K. Mechanism of the inhibitory effect of OPB-9195 [(±)-2-isopropylidenehydrazoneo-4-oxo-thaizolidin-5-ylactenilide] on advanced glycation endproduct and advanced lipoxidation end product formation. J Am Soc Nephrol 2000; 11: 1719-1725
    PubMedSearch in Google Scholar
  • 24 Schlotterer A, Kukudov G, Bozorgmehr F, Hutter H, Du X, Oikonomou D, Ibrahim Y, Pfisterer F, Rabbani N, Thornalley P, Sayed A, Fleming T, Humpert P, Schwenger V, Zeier M, Hamann A, Stern D, Brownlee M, Bierhaus A, Nawroth P. C. elegans as model for the study of high glucose-mediated life span reduction. Diabetes 2009; 58: 2450-2456
    CrossrefPubMedSearch in Google Scholar
  • 25 Reddy VP, Garrett MR, Perry G, Smith MA. Carnosine: a versatile antioxidant and antiglycating agent. Sci Aging Knowl Environ 2005; 2005: 12
    PubMedSearch in Google Scholar
  • 26 Buettner GR. In the absence of catalytic metals ascorbate does not autoxidize at pH 7: ascorbate as a test for catalytic metals. J Biochem Biophys Methods 1988; 16: 27-40
    CrossrefPubMedSearch in Google Scholar
  • 27 Wallin B, Rosengren B, Shertzer HG, Camejo G. Lipoprotein oxidation and measurement of thiobarbituric acid reacting substances formation in a single microtiter plate: its use for evaluation of antioxidants. Anal Biochem 1993; 208: 10-15
    CrossrefPubMedSearch in Google Scholar
  • 28 Upadhyay A, Chompoo J, Taira N, Fukuta M, Tawata S. Significant longevity-extending effects of Alpinia zerumbet leaf extracts on the life span of Caenorhabditis elegans . Biosci Biotechnol Biochem 2013; 77: 217-223
    CrossrefPubMedSearch in Google Scholar