Planta Med 2006; 72(12): 1100-1116
DOI: 10.1055/s-2006-947227
Review
© Georg Thieme Verlag KG Stuttgart · New York

Boswellic Acids in Chronic Inflammatory Diseases

H. P. T. Ammon1
  • 1Dept. of Pharmacology, Institute of Pharmaceutical Sciences, University of Tuebingen, Tuebingen, Germany
In memory of Professor Ernst Reinhard
Further Information

Publication History

Received: April 24, 2006

Accepted: June 15, 2006

Publication Date:
28 August 2006 (online)

Abstract

Oleogum resins from Boswellia species are used in traditional medicine in India and African countries for the treatment of a variety of diseases. Animal experiments showed anti-inflammatory activity of the extract. The mechanism of this action is due to some boswellic acids. It is different from that of NSAID and is related to components of the immune system. The most evident action is the inhibition of 5-lipoxygenase. However, other factors such as cytokines (interleukins and TNF-α) and the complement system are also candidates. Moreover, leukocyte elastase and oxygen radicals are targets. Clinical studies, so far with pilot character, suggest efficacy in some autoimmune diseases including rheumatoid arthritis, Crohn’s disease, ulcerative colitis and bronchial asthma. Side effects are not severe when compared to modern drugs used for the treatment of these diseases.

Abbreviations

AKBA:Acetyl-11-keto-β-boswellic acid

BA:Boswellic acid

BE:Extract from oleogum resin of Boswellia serrata

BS:Boswellia serrata

BSA:Bovine serum albumin

[Ca2+]:Cytosolic calcium concentration

CHE:Cholinesterase

Con A:Concanavalin A

COX1:Cyclooxygenase 1

COX2:Cyclooxygenase 2

cPLA:Phospholipase A

CRP:C-reactive protein

EC50:Effective concentration 50

ESR:Erythrocyte sedimentation rate

FEV1:Forced expiratory volume in 1 sec (liters)

FLAP:5-Lipoxygenase activating protein

fMLP:n-Formyl-methionyl-leucyl-phenylalanin

FVC:Forced vital capacity (liters)

HAB:Homöopathisches Arzneibuch
(German homeopathic pharmacopoeia)

5-HETE:5-Hydroxyeicosatetraenoic acid

12-HETE:12-Hydroxyeicosatetraenoic acid

12-HHT:12-Hydroxyheptadecatrienoic acid

HLE:Human leucocyte elastase

IC50:Inhibitory concentration 50

5-LO:5-Lipoxygenase

IKK:IκBα kinase

IL-1:Interleukin-1

IL-2:Interleukin-2

KBA:11-Keto-β-boswellic acid

LPS:Lipopolysaccharide

LTB4:Leukotriene B4

LTC4:Leukotriene C4

LTD4:Leukotriene D4

LTE4:Leukotriene E4

MAPK:Mitogen activated protein kinase

MCH:Mean corpuscular haemoglobin

MCHC:Mean corpuscular haemoglobin concentration

MCV:Mean corpuscular volume

MEK:Mitogen activated protein kinase kinase

NSAID:Non-steroidal anti-inflammatory drug

P38:p38 kinase

P42:p42 kinase

PEFR:Peak expiratory flowrate

PGF 1α:Prostaglandin F 1α

PHA:Phytohaemagglutinin

PI3-K:Phosphatidylinositol 3-kinase

PMNs:Polymorphonuclear neutrophils

RAS:21 kDA-GTP-binding protein

TA:Tirucallic acid

TH1:T-Helper cells 1

TH2:T-Helper cells 2

TNFα:Tumor necrosis factor α

References

  • 1 Martinez D, Lohs K, Janzen J. Weihrauch und Myrrhe. Kulturgeschichte und wirtschaftliche Bedeutung. Botanik, Chemie, Medizin. Stuttgart; Wissenschaftliche Verlagsgesellschaft 1989
  • 2 Kreck C, Saller R. Indischer Weihrauch und seine Zubereitungen einschließlich H15 als traditionelles und modernes Therapeutikum.  Internist Prax. 1998;  38 857-72
  • 3 Büchele B, Zugmaier W, Simmet T h. Analysis of pentacyclic triterpenic acids from frankincense gum resins and related phytopharmaceuticals by high-performance liquid chromatography. Identification of lupeolic acid, a novel pentacyclic triterpene.  J Chromatogr B. 2003;  791 21-30
  • 4 Beisner K, Büchele B, Werz U, Simmet T h. Structural analysis of 3-α-acetyl-20(29)-lupene-24-oic acid, a novel pentacyclic triterpene isolated from the gum resin of Boswellia serrata, by NMR spectroscopy.  Magn Reson Chem. 2003;  41 629-32
  • 5 Ennet D, Poetsch F, Gröditsch D S ch. Indischer Weihrauch.  Dtsch Apoth Ztg. 2000;  140 105-13
  • 6 Ganzera M, Khan I A. A reversed phase high performance liquid chromatography method for the analysis of boswellic acids in Boswellia serrata .  Planta Med. 2001;  67 778-80
  • 7 Hamm S, Bleton J, Connan J, Tchapla A. A chemical investigation by headspace SPME and GC-MS of volatile and semi-volatile terpenes in various olibanum samples.  Phytochemistry. 2005;  66 1499-514
  • 8 Boden S E, Schweizer S, Bertsche T h, Dufer M, Drews G, Safayhi H. Stimulation of leukotriene synthesis in intact polymorphonuclear cells by the 5-lipoxygenase inhibitor 3-oxotirucallic acid.  Mol Pharmacol. 2001;  60 267-73
  • 9 Singh G B, Atal C K. Pharmacology of an extract of salai guggal ex Boswellia serrata, a new non-steroidal anti-inflammatory agent.  Agents Actions. 1986;  18 407-12
  • 10 Duwiejua M, Zeitlin I J, Waterman P G, Chapman J, Mhango G, Provan G J. Anti-inflammatory activity of resins from some species of the plant family Burseraceae.  Planta Med. 1993;  59 12-6
  • 11 Fan A Y, Lao L, Zhang R X, Wang L B, Lee D Y, Ma Z Z. et al . Effects of an acetone extract of Boswellia carterii Birdw. (Burseraceae) gum resin on rats with persistent inflammation.  J Altern Complement Med. 2005;  11 323-31
  • 12 Gupta O P, Sharma N, Chand D. A sensitive and relevant model for evaluating anti-inflammatory activity-papaya latex-induced rat paw inflammation.  J Pharmacol Toxicol Methods. 1992;  28 15-9
  • 13 Safayhi H, Mack T h, Sabieraj J, Anazodo M I, Subramanian L R, Ammon H P. Boswellic acids: novel, specific, nonredox inhibitors of 5-lipoxygenase.  J Pharmacol Exp Ther. 1992;  261 1143-6
  • 14 Sharma M L, Kaul A, Khajuria A, Singh S, Singh G B. Immunomodulatory activity of boswellic acids (pentacyclic triterpene acids) from Boswellia serrata .  Phytother Res. 1996;  10 107-12
  • 15 Kar A, Menon M K. Analgesic effects of the gum resin of Boswellia serrata Roxb.  Life Sci. 1969;  8 1023-8
  • 16 Menon M K, Kar A. Analgesic and psychopharmacolocigal effects of the gum resin of Boswellia serrata .  Planta Med. 1971;  19 333-41
  • 17 Wagner H, Knaus W, Jordan E. Pflanzeninhaltsstoffe mit Wirkung auf das Komplementsystem.  Z Phytother. 1987;  8 148-9
  • 18 Kapil A, Moza N. Anticomplementary activity of Boswellia acids-an inhibitor of C3-convertase of the classical complement pathway.  Int J Immunopharmacol. 1992;  14 1139-43
  • 19 Badria F A, Mikhaeil B R, Maatooq G T, Amer M M. Immunmodulatory terpenoids from the oleogum resin of Boswellia carterii Birdwood.  Z Naturforsch. 2003;  58 506-16
  • 20 Dahmen U, Gu Y L, Dirsch O, Fan L M, Li J, Shen K. et al . Boswellic acid, a potent anti-inflammatory drug, inhibits rejection to the same extent as high dose steroids.  Transplant Proc. 2001;  33 539-41
  • 21 Pungle P, Banavalikar M, Suthar A, Biyani M, Mengi S. Immunomodulatory activity of boswellic acids of Boswellia serrata Roxb.  Indian J Exp Biol. 2003;  41 1460-2
  • 22 Ammon H P, Mack T, Singh G B, Safayhi H. Inhibition of leukotriene B4 formation in rat peritoneal neutrophils by an ethanolic extract of the gum resin exudate of Boswellia serrata .  Planta Med. 1991;  57 203-7
  • 23 Ammon H P, Safayhi H, Mack T, Sabieraj J. Mechanism of anti-inflammatory actions of curcumine and boswellic acids.  J Ethnopharmacol. 1993;  38 113-9
  • 24 Sailer ER‚ Subramanian L R, Rall B, Hoernlein R F, Ammon H P, Safayhi H. Acetyl-11-keto-beta-boswellic acid (AKBA): structure requirements for binding and 5-lipoxygenase inhibitory activity.  Brit J Pharmacol. 1996;  117 615-8
  • 25 Safayhi H, Sailer E R, Ammon H P. Mechanism of 5-lipoxygenase inhibition by acetyl-11-keto-beta-boswellic acid.  Mol Pharmacol. 1995;  47 1212-6
  • 26 Sailer E R, Schweizer S, Boden S E, Ammon H P, Safayhi H. Characterization of an acetyl-11-keto-beta-boswellic acid and arachidonate-binding regulatory site of 5-lipoxigenase using photoaffinity labeling.  Eur J Biochem. 1998;  256 364-8
  • 27 Boden S E, Bertsche T h, Ammon H P, Safayhi H. MEK-1/2 inhibition prevents 5-lipoxygenase translocation in N-formylpeptide-challenged human neutrophils.  Int J Biochem Cell Biol. 2000;  32 1069-74
  • 28 Altmann A, Fischer L, Schubert-Zsilavecz M, Steinhilber D, Werz O. Boswellic acids activate p42(MAPK) and p38(MAPK) and stimulate Ca(2+) mobilization.  Biochem Biophys Res Commun. 2002;  290 185-90
  • 29 Altmann A, Poeckel D, Fischer L, Schubert-Zsilavecz M, Steinhilber D, Werz O. Coupling of boswellic acid-induced Ca2+ mobilisation and MAPK activation to lipid metabolism and peroxide formation in human leucocytes.  Br J Pharmacol. 2004;  141 223-32
  • 30 Safayhi H, Boden S E, Schweizer S, Ammon H P. Concentration-dependent potentiating and inhibitory effects of Boswellia extracts on 5-lipoxygenase product formation in stimulated PMNL.  Planta Med. 2000;  66 110-3
  • 31 Zarini S, Gijon M A, Folco G, Murphy R C. Effect of arachidonic acid reacylation on leukotriene biosynthesis in human neutrophils stimulated with granulocyte-macrophage colony stimulating factor and formyl-methionyl-leucyl phenylalanine.  J Biol Chem. 2006;  281 10 134-42
  • 32 Schweizer S, von Brocke A F, Boden S E, Bayer E, Ammon H P, Safayhi H. Workup-dependent formation of 5-lipoxygenase inhibitory boswellic acid analogues.  J Nat Prod. 2000;  63 1058-61
  • 33 Bernstein P R, Edwards P D, Williams J C. Inhibitors of human leukocyte elastase.  Med Chem. 1994;  37 59-120
  • 34 Sauer A, Aigner J, Hartung T, Minuth W, Wendel A. Granulocyte mediated hepatotoxicity after endotoxin stimulation depends on adhesion and elastase release.  Naunyn Schmiedebergs Arch Pharmacol. 1995;  351S A495
  • 35 Safayhi H, Rall B, Sailer E R, Ammon H P. Inhibition by boswellic acids of human leukocyte elastase.  J Pharmacol Exp Ther. 1997;  281 460-3
  • 36 Heil K, Ammon H P, Safayhi H. Inhibition of NADPH-oxidase by AKBA in intact PMNs.  Naunyn Schmiedebergs Arch Pharmacol. 2001;  363S R14
  • 37 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 kinase.  J Immunol. 2005;  174 498-506
  • 38 Roy S, Khanna S, Shah H, Rink C, Phillips C, Preuss H. et al . Human genome screen to identify the genetic basis of the anti-inflammatory effects of Boswellia in microvascular endothelial cells.  DNA Cell Biol. 2005;  24 244-55
  • 39 Chervier M R, Ryan A E, Lee D Y, Zhongze M, Wu-Yan Z, Via C S. Boswellia carterii extract inhibits TH1 cytokines and promotes TH2 cytokines in vitro .  Clin Diagn Lab Immunol. 2005;  12 575-80
  • 40 Buchele B, Simmet T. Analysis of 12 different pentacyclic triterpenic acids from frankincense in human plasma by high performance liquid chromatography and photodiode array detection.  J Chromatogr B. 2003;  795 355-62
  • 41 Sharma S, Thawani V, Hingorani L, Shrivastava M, Bhate V R, Khiyani R. Pharmacokinetic study of 11-keto beta-boswellic acid.  Phytomedicine. 2004;  11 255-60
  • 42 Ritschel W A. The handbook of basic pharmacokinetics. 2nd edition Washington; Drug Intelligence Publications, Inc 1980
  • 43 Sterk V, Buchele B, Simmet T. Effect of food intake on the bioavailability of boswellic acids from a herbal preparation in healthy volunteers.  Planta Med. 2004;  70 1155-60
  • 44 Reising K, Meins J, Bastian B, Eckert G, Mueller W E, Schubert-Zsilavecz M. et al . Determination of boswellic acids in brain and plasma by high-performance liquid chromatography/tandem mass spectrometry.  Anal Chem. 2005;  77 6640-5
  • 45 Kesava Reddy G, Dhar S C, Singh G B. Urinary excretion of connective tissue metabolites under the influence of a new non-steroidal anti-inflammatory agent in adjuvant induced arthritis.  Agents Actions. 1987;  22 99-105
  • 46 Sharma M L, Bani S, Singh G B. Anti-arthritic activity of boswellic acids in bovine serum albumin (BSA)-induced arthritis.  Int J Immunopharmacol. 1989;  11 647-52
  • 47 Fukada T, Mogami A, Tanaka H, Yoshikawa T, Hisadome M, Komatsu H. Y-40 138, a multiple cytokine production modulator, protects against D-galactosamine and lipopolysaccharide-induced hepatitis. Life Sci, in press
  • 48 Safayhi H, Mack T h, Ammon H P. Protection by boswellic acids against galactosamine/endotoxin-induced hepatitis in mice.  Biochem Pharmacol. 1991;  41 1536-37
  • 49 Thews G, Mutschler E, Vaupel M A. Anatomie, Physiologie, Pathophysiologie des Menschen. 5th edition Stuttgart; Wissenschaftliche Verlagsgesellschaft 1999: p 599
  • 50 Etzel R. Special extract of Boswellia serrata (H 15) in the treatment of rheumatoid arthritis.  Phytomedicine. 1996;  3 91-4
  • 51 Sander O, Herborn G, Rau R. Is H15 (extract of Boswellia serrata, ”incense”) an efficient supplementation to established drug therapy of rheumatoid arthritis? Results of a double-blind pilot trial.  Z Rheumatol. 1998;  57 11-6
  • 52 Kimmatkar N, Thawani V, Hingorani L, Khiyani R. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee-a randomized double blind placebo controlled trial.  Phytomedicine. 2003;  10 3-7
  • 53 Peskar E M. Inhibition of intestinal leukotriene formation as a possible mechanism of action of sulfosalazine, 5-aminosalicylic acid and 4-aminosalicylic acid.  Klin Wochenschr. 1988;  66 1147-50
  • 54 Stange E F, Schreiber S. Morbus Crohn und Colitis ulcerosa.  Dtsch Ärztebl. 1997;  94 1493-9
  • 55 Gupta I, Parihar A, Malhotra P, Singh G B, Ludtke R, Safayhi H. et al . Effects of Boswellia serrata gum resin in patients with ulcerative colitis.  Eur J Med Res. 1997;  2 37-43
  • 56 Anthoni C, Laukoetter M G, Rijcken E, Vowinkel T, Mennigen R, Muller S. et al . Mechanisms underlying the anti-inflammatory actions of boswellic acid derivatives in experimental colitis.  Am J Physiol Gastrointest Liver Physiol. 2006;  290 G1131-7
  • 57 Kiela P R, Midura A J, Kuscuoglu N, Jolad S D, Solyom A M, Besselsen D G. et al . Effects of Boswellia serrata in mouse models of chemically induced colitis.  Am J Physiol Gastrointest Liver Physiol. 2005;  288 G798-808
  • 58 Kriegelstein C F, Anthoni C, Rijcken E JM, Laukötter M, Spiegel H U, Boden S E. et al . Acetyl-11-keto-β-boswellic acid, a constituent of a herbal medicine from Boswellia serrata resin, attenuates experimental ileitis.  Int J Colorect Dis. 2001;  16 88-95
  • 59 Singh G B, Singh S, Bani S. Alcoholic extract of salai-guggal ex Boswellia serrata, a new natural source NSAID.  Drugs Today. 1996;  32 109-12
  • 60 Gupta I, Parihar A, Malhorta P, Gupta S, Ludtke R, Safayhi H. et al . Effects of gum resin of Boswellia serrata in patients with chronic colitis.  Planta Med. 2001;  67 391-5
  • 61 Madisch A, Miehlke S, Eichele O, Bethke B, Mrwa J, Kuhlisch E. et al . Boswellia serrata Extrakt bei kollagener Kolitis - eine randomisierte, placebo-kontrollierte, doppelblinde Multicenterstudie. Dtsch Ges Verdau Stoffw Erkr Suppl.  Z Gastroenterol. 2005;  43 P061
  • 62 Gerhardt H, Seifert F, Buvari P, Vogelsang H, Repges R Z. Therapie des aktiven Morbus Crohn mit Boswellia serrata Extract H 15.  Z Gastroenterol. 2001;  39 11-7
  • 63 Chanarin N, Johnston S L. Leukotrienes as a target in asthma therapy.  Drugs. 1994;  47 12-24
  • 64 Gupta I, Gupta V, Parihar A, Gupta S Ludtke R, Safayhi H. et al . Effects of Boswellia serrata gum resin in patients with bronchial asthma: results of a double-blind, placebo-controlled, 6 week clinical study.  Eur J Med Res. 1998;  3 511-4
  • 65 Wildfeuer A, Neu I S, Safayhi H, Metzger G, Wehrmann M, Vogel U. et al . Effects of boswellic acids extracted from a herbal medicine on the biosynthesis of leukotrienes and the course of experimental autoimmune encephalomyelitis.  Drug Res. 1998;  48 668-74
  • 66 Böker D K, Winking M. Die Rolle von Boswellia-Säuren in der Therapie maligner Gliome.  Dtsch Ärztebl. 1997;  94 B-958 - 60
  • 67 Streffer J R, Bitzer M, Schabet M, Dichgans J, Weller M. Response of radiochemotherapy-associated cerebral edema a phytotherapeutic agent, H15.  Neurology. 2001;  56 1219-21
  • 68 Buvari P G. Wirksamkeit und Unbedenklichkeit der H15 Ayurmedica-Therapie bei chronisch entzündlichen Erkrankungen [dissertation]. Mannheim-Heidelberg; University of Mannheim-Heidelberg 2001
  • 69 Basch E, Boon H, Davies-Heerema T, Foppo I, Hashme S, Hasskarl J. et al . Boswellia: an evidence-based systematic review by the Natural Standard Research Collaboration.  J Herb Pharmacother. 2004;  4 63-83

Prof. H. P. T. Ammon

Pharmakologie

Universität Tübingen

Auf der Morgenstelle 8

72076 Tuebingen

Germany

Phone: +49-7071-297-4675

Fax: +49-7071-392-476

Email: sekretariat.ammon@uni-tuebingen.de

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