Download PDF
Planta Med 2013; 79(03/04): 214-218
DOI: 10.1055/s-0032-1328090
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Alkamides from Echinacea angustifolia Interact with P-Glycoprotein of Primary Brain Capillary Endothelial Cells Isolated from Porcine Brain Blood Vessels

Anne Mahringer   *
1   Institute of Pharmacy and Molecular Biotechnology, Department of Pharmaceutical Technology and Pharmacology, University of Heidelberg, Heidelberg, Germany
,
Karin Ardjomand-Woelkart   *
2   Institute of Pharmaceutical Sciences, Department of Pharmacognosy, Karl-Franzens-University Graz, Graz, Austria
,
Rudolf Bauer
2   Institute of Pharmaceutical Sciences, Department of Pharmacognosy, Karl-Franzens-University Graz, Graz, Austria
,
Gert Fricker
1   Institute of Pharmacy and Molecular Biotechnology, Department of Pharmaceutical Technology and Pharmacology, University of Heidelberg, Heidelberg, Germany
,
Thomas Efferth
3   Institute of Pharmacy and Biochemistry, Department of Pharmaceutical Biology, Johannes Gutenberg University, Mainz, Germany
› Author Affiliations
Further Information

Publication History

received 13 July 2012
revised 29 November 2012

accepted 04 December 2012

Publication Date:
15 January 2013 (online)

    Permissions and Reprints

Abstract

The blood-brain barrier prevents the passage of toxic compounds from blood circulation into brain tissue. Unfortunately, drugs for the treatment of neurodegenerative diseases, brain tumors, and other diseases also do not cross the blood-brain barrier. In the present investigation, we used isolated porcine brain capillary endothelial cells and a flow cytometric calcein-AM assay to analyze inhibition of P-glycoprotein, a major constituent of the blood-brain barrier. We tested 8 alkamides isolated from Echinacea angustifolia and found that four of them inhibited P-glycoprotein-mediated calcein transport in porcine brain capillary endothelial cells.

Key words

ABC transporter - alkamides - blood-brain barrier - Echinacea angustifolia - Asteraceae - P-glycoprotein - inhibitor

* Both authors contributed equally to this work.


 

  • References

  • 1 Ballabh P, Braun A, Nedergaard M. The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 2004; 16: 1-13
    CrossrefPubMedGoogle Scholar
  • 2 Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATB binding cassette (ABC) family: an overview. Adv Drug Deliv Rev 2003; 55: 3-29
    CrossrefPubMedGoogle Scholar
  • 3 Pardrige WM. CNS drug design based on principles of blood-brain barrier transport. J Neurochem 1998; 70: 1781-1792
    PubMedGoogle Scholar
  • 4 Woelkart K, Frye RF, Derendorf H, Bauer R, Butterweck V. Pharmacokinetics and tissue distribution of dodeca-2E,4E,8E,10E/Z-tetraenoic acid isobutlyamides after oral administration in rats. Planta Med 2009; 75: 1306-1313
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Tiwari AK, Sodani K, Dai CL, Ashby Jr. CR, Chen ZS. Revisiting the ABCs of multidrug resistance in cancer chemotherapy. Curr Pharm Biotechnol 2010; 12: 570-594
    PubMedGoogle Scholar
  • 6 Adams M, Mahringer A, Bauer R, Fricker G, Efferth T. In vitro cytotoxicity and P-glycoprotein modulating effects of geranylated furocoumarins from Tetradium daniellii . Planta Med 2007; 73: 1475-1478
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Adams M, Mahringer A, Kunert O, Fricker G, Efferth T, Bauer R. Cytotoxicity and p-glycoprotein modulating effects of quinolones and indoloquinazolines from the Chinese herb Evodia rutaecarpa . Planta Med 2007; 73: 1554-1557
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Mahringer A, Karamustafa S, Klotz D, Kahl S, Konkimalla VB, Wang Y, Wang J, Liu HY, Boechzelt H, Hao X, Bauer R, Fricker G, Efferth T. Inhibition of P-glycoprotein at the blood-brain barrier by phytochemicals derived from traditional Chinese medicine. Cancer Genom Proteom 2010; 7: 191-205
    PubMedGoogle Scholar
  • 9 Bauer R, Remiger P, Wagner H. Alkamides from the roots of Echinacea angustifolia . Phytochemistry 1989; 28: 505-508
    CrossrefPubMedGoogle Scholar
  • 10 Huwyler J, Drewe J, Klusemann C, Fricker G. Evidence for P-glycoprotein-modulated penetration of morphine-6-glucuronide into brain capillary endothelium. Br J Pharmacol 1996; 118: 1879-1885
    CrossrefPubMedGoogle Scholar
  • 11 Bauer B, Miller DS, Fricker G. Compound profiling for P-glycoprotein at the blood-brain barrier using a microplate screening system. Pharm Res 2003; 20: 1170-1176
    CrossrefPubMedGoogle Scholar
  • 12 Eneroth A, Astrom E, Hoogstraate J, Schrenk D, Conrad S, Kauffmann HM, Gjellan K. Evaluation of a vincristine resistant Caco-2 cell line for use in a calcein AM extrusion screening assay for P-glycoprotein interaction. Eur J Pharm Sci 2001; 12: 205-214
    CrossrefPubMedGoogle Scholar
  • 13 Lemaire M, Bruelisauer A, Guntz P, Sato H. Dose-dependent brain penetration of SDZ PSC 833, a novel multidrug resistance reversing cyclosporin in rats. Cancer Chemother Pharmacol 1996; 38: 481-486
    CrossrefPubMedGoogle Scholar
  • 14 Tiberghien F, Loor F. Ranking of p-glycoprotein substrates and inhibitors by a calcein-AM fluorometry screening assay. Anticancer Drugs 1996; 7: 568-578
    CrossrefPubMedGoogle Scholar
  • 15 Melchart D, Linde K, Fischer P, Kaesmayr J. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev 2000; (2) CD000530 Update in: Cochrane Database Syst Rev 2006; (1) CD000530
    PubMedGoogle Scholar
  • 16 Caruso TJ, Gwaltney Jr. JM. Treatment of the common cold with Echinacea: a structured review. Clin Infect Dis 2005; 40: 807-810
    CrossrefPubMedGoogle Scholar
  • 17 Basch E, Ulbricht C, Basch S, Dalton S, Ernst E, Foppa I, Szapary P, Tiffany N, Orlando CW, Vora M. An evidence-based systemic review Echinacea. E. angustifolia DC, E. pallida, E. purpurea by the Natural Standard Research Collaboration. J Herb Pharmacother 2005; 5: 57-88
    PubMedGoogle Scholar
  • 18 Linde K, Barrett B, Wölkart K, Bauer R, Melchart D. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev 2006; (1) CD000530
    PubMedGoogle Scholar
  • 19 Shah SA, Sander S, White CM, Rinaldi M, Coleman CI. Evaluation of Echinacea for the prevention and treatment of the common cold: a meta-analysis. Lancet Infect Dis 2007; 7: 473-480 Erratum in: Lancet Infect Dis 2007; 7: 580 Erratum in: Lancet Infect Dis 2007; 7: 580
    CrossrefPubMedGoogle Scholar
  • 20 Woelkart K, Linde K, Bauer R. Echinacea for preventing and treating the common cold. Planta Med 2008; 74: 633-637
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Woelkart K, Bauer R. The role of alkamides as an active principle of Echinacea . Planta Med 2007; 73: 615-623
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Gurley BJ, Swain A, Williams DK, Barone G, Battu SK. Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: comparative effects of St. Johnʼs wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics. Mol Nutr Food Res 2008; 52: 772-779
    CrossrefPubMedGoogle Scholar
  • 23 Romiti N, Pellati F, Nieri P, Benvenuti S, Adinolfi B, Chieli E. P-Glycoprotein inhibitory activity of lipophilic constituents of Echinacea pallida roots in a human proximal tubular cell line. Planta Med 2008; 74: 264-266
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Hansen TS, Nilsen OG. Echinacea purpurea and P-glycoprotein drug transport in caco-2 cells. Phytother Res 2009; 23: 86-91
    CrossrefPubMedGoogle Scholar
  • 25 Rautio J, Humphreys JE, Webster LO. In vitro P-glycoprotein inhibition assays for assessment of clinical drug interaction potential of new drug candidates: a recommendation for probe substrates. Drug Metab Dispos 2006; 34: 786-792
    CrossrefPubMedGoogle Scholar
  • 26 Loo TW, Bartlett MC, Clarke DM. Val133 and Cys137 in transmembrane segment 2 are close to Arg935 and Gly939 in transmembrane segment 11 of human P-glycoprotein. J Biol Chem 2004; 279: 18232-18238
    CrossrefPubMedGoogle Scholar
  • 27 Ramu A, Pollard HB, Rosario LM. Doxorubicin resistance in P388 leukemia–evidence for reduced drug influx. Int J Cancer 1989; 44: 539-547
    CrossrefPubMedGoogle Scholar
  • 28 Raduner S, Bisson W, Abagyan R, Altmann KH, Gertsch J. Self-assembling cannabinomimetics: supramolecular structures of N-alkyl amides. J Nat Prod 2007; 70: 1010-1015
    CrossrefPubMedGoogle Scholar
  • 29 Woelkart K, Koidl C, Grisold A, Gangemi JD, Turner RB, Marth E, Bauer R. Bioavailability and pharmacokinetics of alkamides from the roots of Echinacea angustifolia in humans. J Clin Pharmacol 2005; 45: 683-689
    CrossrefPubMedGoogle Scholar