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Horm Metab Res 2015; 47(06): 463-469
DOI: 10.1055/s-0035-1547293
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

11-Keto-β-Boswellic Acids Prevent Development of Autoimmune Reactions, Insulitis and Reduce Hyperglycemia During Induction of Multiple Low-Dose Streptozotocin (MLD-STZ) Diabetes in Mice

A. M. Shehata
1   Department of Pharmacology, Institute of Pharmaceutical Sciences, University of Tübingen, Tübingen, Germany
2   Department of Pharmacology, Faculty of Pharmacy, Beni-Sueif University, Bani Suwayf, Egypt
,
L. Quintanilla-Fend
3   Institute of Pathology, University of Tübingen, Tübingen, Germany
,
S. Bettio
3   Institute of Pathology, University of Tübingen, Tübingen, Germany
,
J. Jauch
4   Institute of Pharmaceutical Sciences, University of Saarland, Saarbrücken, Germany
,
T. Scior
5   Department of Pharmacy, Faculty of Chemical Sciences, BUAP, Mexico
,
W. A. Scherbaum
6   Heinrich-Heine-University, University Hospital, Düsseldorf, Germany
,
H. P. T. Ammon
7   Department of Pharmacology, Institute of Pharmaceutical Sciences, University of Tübingen, Tübingen, Germany
› Author Affiliations
Further Information

Publication History

received 06 January 2015

accepted 26 February 2015

Publication Date:
07 May 2015 (online)

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Abstract

The aim of the work was to study whether or not 11-keto-β-boswellic acids prevent induction of autoimmune reactions, insulitis, and hyperglycemia in the model of multiple low-dose streptozotocin (MLD-STZ) diabetes. Using male mice (n=6) diabetes was induced by daily i.p. injections of 40 mg/kg STZ for 5 days. In a second series together with STZ, daily i. p. injections of 11-keto-β-boswellic acid (KBA) and O-acetyl-11-keto-β-boswellic acid (AKBA) (7.5 and 15.0 mg/kg) were applied for 10 days. Thereafter, pro-and anti-inflammatory cytokines in the blood, histochemistry of pancreatic islets, and blood glucose levels were assayed. Five days after the last injection of STZ, a significant burst of pro-and anti-inflammatory cytokines in the blood, infiltration of lymphocytes (CD3) into pancreatic islets, and appearance of peri-insular apoptotic cells were observed. Plasma glucose increased significantly (124.4±6.65 vs. 240.2±27.36 mg/dl, p<0.05). Simultaneous treatment with KBA and AKBA significantly reduced pro-and anti-inflammatory cytokines (IFN-γ p<0.01, p<0.01; IL-1A p<0.001, p<0.001; IL-1B p<0.001, p<0.001; IL-2 p<0.001, p<0.001; IL-6 p<0.01, p<0.001; TNF-α p<0.05, p<0.001; IL-4 p<0.01, p<0.001; IL-10 p<0.001, p<0.001) in the blood. No infiltration of lymphocytes into pancreatic islets and appearance of peri-insular cells were detected. Moreover, KBA and AKBA reduced STZ-mediated increase of blood glucose on day 10 to 163.25±16.6 (p<0.05) and 187.6±19.5 mg/dl (p<0.05), respectively. In the model of MLD-STZ induced diabetes KBA and AKBA prevent cytokine burst, development of insulitis and reduce increase of blood glucose through “silencing” a forced-up immune reaction.

Key words

boswellic acids - multiple low dose streptozotocin diabetes - prevention - insulitis - histochemistry - cytokines
 

  • References

  • 1 McEvoy RC, Andersson J, Sandler S, Hellerström C. Multiple low-dose streptozotocin-induced diabetes in the mouse. Evidence for stimulation of a cytotoxic cellular immune response against an insulin-producing beta cell line. J Clin Invest 1984; 74: 715-722
    CrossrefPubMedGoogle Scholar
  • 2 Castano L, Eisenbarth GS. Type-1 diabetes: A chronic autoimmune disease of human, mouse and rat. Annu Rev Immunol 1990; 8: 647-679
    CrossrefPubMedGoogle Scholar
  • 3 Lukic’ ML, Stosic-Grujicic’ S, Shahin A. Effector mechanisms in low-dose streptozotocin-induced diabetes. Dev Immunol 1998; 6: 119-128
    CrossrefPubMedGoogle Scholar
  • 4 Herold KC, Vezys V, Sun Q, Viktora D, Seung E, Reiner S, Brown D. Regulation of cytokine production during development of autoimmune diabetes induced with multiple low doses of streptozotocin. Immunol 1996; 156: 3521-3527
    PubMedGoogle Scholar
  • 5 Ammon HPT. Modulation of the immune system by Boswellia serrata extracts and boswellic acids. Phytomed 2010; 17: 862-867
    CrossrefPubMedGoogle Scholar
  • 6 Ammon HPT. Boswellic acids in chronic inflammatory diseases. Planta Med 2006; 72: 1100-1116
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Syrovets T, Büchele B, Krauss Ch. Acetyl-boswellic acids inhibit lipopolysaccharide-mediated TNF-α induction in monocytes by direct interaction with IκB kinases. Immunol 2005; 174: 498-506
    CrossrefPubMedGoogle Scholar
  • 8 Shehata AM, Quintanilla-Fend L, Bettio S, Singh CB, Ammon HPT. Prevention of multiple low-dose streptozotocin (MLD-STZ) diabetes in mice by an extract from gum resin of Boswellia serrata (BE). Phytomed 2011; 18: 1037-1044
    CrossrefPubMedGoogle Scholar
  • 9 Jauch J, Gergmann J. An efficient method for the larger scale preparation of 3-O-acetyl-11-oxo-β-boswellic acid and other boswellic acids. Eur J Org Chem 2003; 24: 4752-4756
    PubMedGoogle Scholar
  • 10 Kunder S, Calzada-Wack J, Hölzwimmer G, Müller J, Kloss C, Howatt W, Schmidt J, Höfler H, Warren M, Quintanilla-Martinez L. A comprehensive antibody panel for immunohistochemical analysis of formalin-fixed, paraffin-embedded hematopoietic neoplasms of mice: analysis of mouse specific and human antibodies cross-reactive with murine tissue. Toxicol Pathol 2007; 35: 366-375
    CrossrefPubMedGoogle Scholar
  • 11 Wang H, Syrovets T, Kess D, Büchele B, Hainzl H, Lunow O, Weiss JM, Scharffetter-Kochanek K, Simmet T. Targeting NF-kappa B with a natural triterpenoid allivates skin inflammation in a mouse model of psoriasis. J Immunol 2009; 183: 4755-4763
    CrossrefPubMedGoogle Scholar
  • 12 Lenzen S. The mechanism of alloxan- and streptozotocin induced diabetes. Diabetologia 2008; 51: 216-226
    CrossrefPubMedGoogle Scholar
  • 13 Ammon HPT, Shehata AM, Jauch J, Quintanilla-Martinez L. 11-Keto-beta boswellic acid prevents development of insulitis in NOD mice. Diabetologia 2012; 55 (Suppl. 01) S193-S193
    PubMedGoogle Scholar
  • 14 Schneider DA. Potential viral pathogenic mechanism in human type 1 diabetes. Diabetologia 2014; 57: 2009-2018
    CrossrefPubMedGoogle Scholar
  • 15 Kallmann BA, Hüttner M, Tubes M, Feldkamp J, Bertrams J, Gries FA, Lampeter EF, Kolb H. Systemic basis of cytokine production toward cell-mediated immune regulation in IDDM and toward humoral immunity in Graves’ disease. Diabetes 1997; 46: 237-243
    CrossrefPubMedGoogle Scholar
  • 16 Hussain MJ, Peakman M, Galatti H, Lo SS, Hawa M, Viberti GC, Watkins PJ, Lessle RD, Vergani D. Elevated serum levels of macrophage-derived cytokines precede and accompany the onset of IDDM. Diabetologia 1996; 39: 60-69
    PubMedGoogle Scholar
  • 17 Fontbonne A. Markers of inflammation and prediction of diabetes mellitus in adults. Rev Epidemiol Sante Publique 1999; 47: 491-492
    PubMedGoogle Scholar
  • 18 Stechova K, Bohmova K, Vrabelova Z, Sepa A, Stadlerova G, Zacharovova K, Faresjo M. High T-helper-1-cytokines but low T-helper-3 cytokines, inflammatory cytokines and chemokines in children with high risk of developing type 1 diabetes. Diabetes Metab Res Rev 2007; 23: 462-471
    CrossrefPubMedGoogle Scholar
  • 19 Melloul D. Role of NF-kappa B in beta-cell death. Biochem Soc Trans 2008; 36 (Pt 3) 334-339
    CrossrefPubMedGoogle Scholar
  • 20 The Canadian-European Randomized Control Trial Group Cyclosporin-induced remission of IDDM after early intervention . Association of 1 year of cyclosporin treatment with enhanced insulin secretion. Diabetes 1988; 37: 1574-1582
    CrossrefPubMedGoogle Scholar
  • 21 Martin S, Scherntaner G, Nerup J, Gries FA, Kolvisto VA, Dupre J, Standl E, Hamet P, Mc Arthur R, Tan MH, Dawson K, Mehta AE, Van Vliet S, Von Graffenried B, Stiller C, Kolb H. Follow-up of cyclosporin A treatment in type 1 (insulin-dependent) diabetes mellitus: Lack of long-term effects. Diabetologia 1991; 34: 429-434
    CrossrefPubMedGoogle Scholar
  • 22 Herold KC, Gitelmann SE, Masharani U, Hagopian W, Biskrska B, Donaldson D, Rother K, Diamond B, Harlan DM, Bluestonoe JA. A single course of anti-CD3 monoclonal antibody hOKT3 gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 2005; 54: 1763-1769
    CrossrefPubMedGoogle Scholar
  • 23 Keymeulen B, Vandermeulebroucke E, Ziegler AG, Mathieu C, Kaufmann L, Hale G, Gorus F, Goldman M., Walter M, Candon S, Schandene L, Crenier L, De Block C, Seigneurin JM, De Pauw P, Pierard D, Weets I, Repello P, Bird P, Berrie E, Frewin M, Waldmann H, Bach JF, Pipeleers D, Chatenoud L. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005; 352: 2598-2608
    CrossrefPubMedGoogle Scholar
  • 24 Schrott E, Laufer S, Lämmerhofer M, Ammon HPT. Extract from gum resin of Boswellia serrata decreases IA2-antibody in a patient with “Late onset Autoimmune Diabetes of the Adult (LADA)”. Phytomed 2014; 21: 786
    CrossrefPubMedGoogle Scholar