Download PDF
Planta Med 2017; 83(12/13): 1020-1027
DOI: 10.1055/s-0043-107884
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Defined Structure-Activity Relationships of Boswellic Acids Determine Modulation of Ca2+ Mobilization and Aggregation of Human Platelets by Boswellia serrata Extracts[*]

Ulf Siemoneit   **
1   Department of Pharmaceutical Analytics, Pharmaceutical Institute, Eberhard Karls University Tuebingen, Tuebingen, Germany
,
Lars Tausch   **
2   Institute of Pharmaceutical Chemistry, University of Frankfurt, Frankfurt, Germany
,
Daniel Poeckel
1   Department of Pharmaceutical Analytics, Pharmaceutical Institute, Eberhard Karls University Tuebingen, Tuebingen, Germany
,
Michael Paul
3   Institute of Organic Chemistry, University of Saarland, Saarbruecken, Germany
,
Hinnak Northoff
4   Institute for Clinical and Experimental Transfusion Medicine, University Medical Center Tuebingen, Tuebingen, Germany
,
Andreas Koeberle
1   Department of Pharmaceutical Analytics, Pharmaceutical Institute, Eberhard Karls University Tuebingen, Tuebingen, Germany
5   Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Jena, Germany
,
Johann Jauch
3   Institute of Organic Chemistry, University of Saarland, Saarbruecken, Germany
,
Oliver Werz
1   Department of Pharmaceutical Analytics, Pharmaceutical Institute, Eberhard Karls University Tuebingen, Tuebingen, Germany
5   Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Jena, Germany
› Author Affiliations
Further Information

Publication History

received 22 December 2016
revised 15 March 2017

accepted 25 March 2017

Publication Date:
12 April 2017 (online)

    Permissions and Reprints

Abstract

Boswellic acids constitute a group of unique pentacyclic triterpene acids from Boswellia serrata with multiple pharmacological activities that confer them anti-inflammatory and anti-tumoral properties. A subgroup of boswellic acids, characterized by an 11-keto group, elevates intracellular Ca2+ concentrations [Ca2+]i and causes moderate aggregation of human platelets. How different BAs and their mixtures in pharmacological preparations affect these parameters in activated platelets has not been addressed, so far. Here, we show that boswellic acids either antagonize or induce Ca2+ mobilization and platelet aggregation depending on defined structural determinants with inductive effects predominating for a B. serrata gum resin extract. 3-O-Acetyl-11-keto-β-boswellic acid potently suppressed Ca2+ mobilization (IC50 = 6 µM) and aggregation (IC50 = 1 µM) when platelets were activated by collagen or the thromboxane A2 receptor agonist U-46619, but not upon thrombin. In contrast, β-boswellic acid and 3-O-acetyl-β-boswellic acid, which lack the 11-keto moiety, were weak inhibitors of agonist-induced platelet responses, but instead they elicited elevation of [Ca2+]i and aggregation of platelets (≥ 3 µM). 11-Keto-β-boswellic acid, the structural intermediate between 3-O-acetyl-11-keto-β-boswellic acid and β-boswellic acid, was essentially inactive independent of the experimental conditions. Together, our study unravels the complex agonizing and antagonizing properties of boswellic acids on human platelets in pharmacologically relevant preparations of B. serrata gum extracts and prompts for careful evaluation of the safety of such extracts as herbal medicine in cardiovascular risk patients.

Key words

Boswellia serrata - Burseraceae - boswellic acids - platelets - calcium - collagen - aggregation

* Dedicated to Professor Dr. Max Wichtl in recognition of his outstanding contribution to pharmacognosy research.


** These two authors contributed equally to this work.


Supporting information

    Preparation of B. serrata extracts, neutral and acidic fractions, and HPLC analysis thereof as well as quantification of BAs are available as Supporting Information.

  • Supporting Information
 

  • References

  • 1 Ammon HP. Boswellic acids and their role in chronic inflammatory diseases. Adv Exp Med Biol 2016; 928: 291-327
    PubMedGoogle Scholar
  • 2 Abdel-Tawab M, Werz O, Schubert-Zsilavecz M. Boswellia serrata: an overall assessment of in vitro, preclinical, pharmacokinetic and clinical data. Clin Pharmacokinet 2011; 50: 349-369
    CrossrefPubMedGoogle Scholar
  • 3 Hussain H, Al-Harrasi A, Csuk R, Shamraiz U, Green IR, Ahmed I, Khan IA, Ali Z. Therapeutic potential of boswellic acids: a patent review (1990–2015). Expert Opin Ther Pat 2017; 27: 81-90
    CrossrefPubMedGoogle Scholar
  • 4 Tausch L, Henkel A, Siemoneit U, Poeckel D, Kather N, Franke L, Hofmann B, Schneider G, Angioni C, Geisslinger G, Skarke C, Holtmeier W, Beckhaus T, Karas M, Jauch J, Werz O. Identification of human cathepsin G as a functional target of boswellic acids from the anti-inflammatory remedy frankincense. J Immunol 2009; 183: 3433-3442
    CrossrefPubMedGoogle Scholar
  • 5 Safayhi H, Mack T, Sabieraj J, Anazodo MI, Subramanian LR, Ammon HP. Boswellic acids: novel, specific, nonredox inhibitors of 5-lipoxygenase. J Pharmacol Exp Ther 1992; 261: 1143-1146
    PubMedGoogle Scholar
  • 6 Poeckel D, Tausch L, Kather N, Jauch J, Werz O. Boswellic acids stimulate arachidonic acid release and 12-lipoxygenase activity in human platelets independent of Ca2+ and differentially interact with platelet-type 12-lipoxygenase. Mol Pharmacol 2006; 70: 1071-1078
    CrossrefPubMedGoogle Scholar
  • 7 Siemoneit U, Hofmann B, Kather N, Lamkemeyer T, Madlung J, Franke L, Schneider G, Jauch J, Poeckel D, Werz O. Identification and functional analysis of cyclooxygenase-1 as a molecular target of boswellic acids. Biochem Pharmacol 2008; 75: 503-513
    CrossrefPubMedGoogle Scholar
  • 8 Safayhi H, Rall B, Sailer ER, Ammon HP. Inhibition by boswellic acids of human leukocyte elastase. J Pharmacol Exp Ther 1997; 281: 460-463
    PubMedGoogle Scholar
  • 9 Syrovets T, Buchele B, Krauss C, Laumonnier Y, Simmet T. Acetyl-boswellic acids inhibit lipopolysaccharide-mediated TNF-alpha induction in monocytes by direct interaction with IkappaB kinases. J Immunol 2005; 174: 498-506
    CrossrefPubMedGoogle Scholar
  • 10 Siemoneit U, Koeberle A, Rossi A, Dehm F, Verhoff M, Reckel S, Maier TJ, Jauch J, Northoff H, Bernhard F, Doetsch V, Sautebin L, Werz O. Inhibition of microsomal prostaglandin E2 synthase-1 as a molecular basis for the anti-inflammatory actions of boswellic acids from frankincense. Br J Pharmacol 2011; 162: 147-162
    CrossrefPubMedGoogle Scholar
  • 11 Henkel A, Kather N, Monch B, Northoff H, Jauch J, Werz O. Boswellic acids from frankincense inhibit lipopolysaccharide functionality through direct molecular interference. Biochem Pharmacol 2012; 83: 115-121
    CrossrefPubMedGoogle Scholar
  • 12 Henkel A, Tausch L, Pillong M, Jauch J, Karas M, Schneider G, Werz O. Boswellic acids target the human immune system-modulating antimicrobial peptide LL-37. Pharmacol Res 2015; 102: 53-60
    CrossrefPubMedGoogle Scholar
  • 13 Poeckel D, Tausch L, George S, Jauch J, Werz O. 3-O-acetyl-11-keto-boswellic acid decreases basal intracellular Ca2+ levels and inhibits agonist-induced Ca2+ mobilization and mitogen-activated protein kinase activation in human monocytic cells. J Pharmacol Exp Ther 2006; 316: 224-232
    CrossrefPubMedGoogle Scholar
  • 14 Wang M, Chen M, Ding Y, Zhu Z, Zhang Y, Wei P, Wang J, Qiao Y, Li L, Li Y, Wen A. Pretreatment with beta-Boswellic acid improves blood stasis induced endothelial dysfunction: role of eNOS activation. Sci Rep 2015; 5: 15357
    CrossrefPubMedGoogle Scholar
  • 15 Kunnumakkara AB, Nair AS, Sung B, Pandey MK, Aggarwal BB. Boswellic acid blocks signal transducers and activators of transcription 3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase SHP-1. Mol Cancer Res 2009; 7: 118-128
    CrossrefPubMedGoogle Scholar
  • 16 Poeckel D, Werz O. Boswellic acids: biological actions and molecular targets. Curr Med Chem 2006; 13: 3359-3369
    CrossrefPubMedGoogle Scholar
  • 17 Poeckel D, Tausch L, Altmann A, Feisst C, Klinkhardt U, Graff J, Harder S, Werz O. Induction of central signalling pathways and select functional effects in human platelets by beta-boswellic acid. Br J Pharmacol 2005; 146: 514-524
    CrossrefPubMedGoogle Scholar
  • 18 Altmann A, Fischer L, Schubert-Zsilavecz M, Steinhilber D, Werz O. Boswellic acids activate p 42(MAPK) and p 38 MAPK and stimulate Ca(2+) mobilization. Biochem Biophys Res Commun 2002; 290: 185-190
    CrossrefPubMedGoogle Scholar
  • 19 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 8: 1227-1234
    CrossrefPubMedGoogle Scholar
  • 20 Comerota AJ, Thakur S. Antiplatelet therapy for vascular interventions. Perspect Vasc Surg Endovasc Ther 2008; 20: 28-35
    CrossrefPubMedGoogle Scholar
  • 21 Thomas MR, Storey RF. The role of platelets in inflammation. Thromb Haemost 2015; 114: 449-458
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Holmsen H. Significance of testing platelet functions in vitro . Eur J Clin Invest 1994; 24: 3-8
    CrossrefPubMedGoogle Scholar
  • 23 Holmsen H. Signal transducing mechanisms in platelets. Proc Natl Sci Counc Repub China B 1991; 15: 147-152
    PubMedGoogle Scholar
  • 24 Kramer RM, Roberts EF, Strifler BA, Johnstone EM. Thrombin induces activation of p 38 MAP kinase in human platelets. J Biol Chem 1995; 270: 27395-27398
    CrossrefPubMedGoogle Scholar
  • 25 Papkoff J, Chen RH, Blenis J, Forsman J. p 42 mitogen-activated protein kinase and p 90 ribosomal S6 kinase are selectively phosphorylated and activated during thrombin-induced platelet activation and aggregation. Mol Cell Biol 1994; 14: 463-472
    CrossrefPubMedGoogle Scholar
  • 26 Tawfik MK. Anti-aggregatory effect of boswellic acid in high-fat fed rats: involvement of redox and inflammatory cascades. Arch Med Sci 2016; 12: 1354-1361
    PubMedGoogle Scholar
  • 27 Heemskerk JW, Bevers EM, Lindhout T. Platelet activation and blood coagulation. Thromb Haemost 2002; 88: 186-193
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Wootton DM, Ku DN. Fluid mechanics of vascular systems, diseases, and thrombosis. Annu Rev Biomed Eng 1999; 1: 299-329
    CrossrefPubMedGoogle Scholar
  • 29 Paul BZ, Jin J, Kunapuli SP. Molecular mechanism of thromboxane A(2)-induced platelet aggregation. Essential role for p2t(ac) and alpha(2a) receptors. J Biol Chem 1999; 274: 29108-29114
    CrossrefPubMedGoogle Scholar
  • 30 Watson SP, Auger JM, McCarty OJ, Pearce AC. GPVI and integrin alphaIIb beta3 signaling in platelets. J Thromb Haemost 2005; 3: 1752-1762
    CrossrefPubMedGoogle Scholar
  • 31 Kruger P, Kanzer J, Hummel J, Fricker G, Schubert-Zsilavecz M, Abdel-Tawab M. Permeation of Boswellia extract in the Caco-2 model and possible interactions of its constituents KBA and AKBA with OATP1B3 and MRP2. Eur J Pharm Sci 2009; 36: 275-284
    CrossrefPubMedGoogle Scholar
  • 32 Kruger P, Daneshfar R, Eckert GP, Klein J, Volmer DA, Bahr U, Muller WE, Karas M, Schubert-Zsilavecz M, Abdel-Tawab M. Metabolism of boswellic acids in vitro and in vivo . Drug Metab Dispos 2008; 36: 1135-1142
    CrossrefPubMedGoogle Scholar
  • 33 Gerbeth K, Husch J, Fricker G, Werz O, Schubert-Zsilavecz M, Abdel-Tawab M. In vitro metabolism, permeation, and brain availability of six major boswellic acids from Boswellia serrata gum resins. Fitoterapia 2013; 84: 99-106
    CrossrefPubMedGoogle Scholar
  • 34 Jauch J, Bergmann J. An efficient method for the large-scale preparation of 3-O-acetyl-11-oxo-beta-boswellic acid and other boswellic acids. Eur J Org Chem 2003; 24: 4752-4756
    PubMedGoogle Scholar
  • 35 Grynkiewicz G, Poenie M, Tsien RY. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 1985; 260: 3440-3450
    PubMedGoogle Scholar