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; L. Quintanilla-Fend; S. Bettio; J. Jauch; T. Scior; W. A. Scherbaum; H. P. T. Ammon

doi:10.1055/s-0035-1547293

Hormone and Metabolic Research, Inhaltsverzeichnis

Horm Metab Res 2015; 47(06): 463-469
DOI: 10.1055/s-0035-1547293

Endocrine Research

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

Autor*innen

A. M. Shehata

¹Department of Pharmacology, Institute of Pharmaceutical Sciences, University of Tübingen, Tübingen, Germany

²Department of Pharmacology, Faculty of Pharmacy, Beni-Sueif University, Bani Suwayf, Egypt
L. Quintanilla-Fend

³Institute of Pathology, University of Tübingen, Tübingen, Germany
S. Bettio

³Institute of Pathology, University of Tübingen, Tübingen, Germany
J. Jauch

⁴Institute of Pharmaceutical Sciences, University of Saarland, Saarbrücken, Germany
T. Scior

⁵Department of Pharmacy, Faculty of Chemical Sciences, BUAP, Mexico
W. A. Scherbaum

⁶Heinrich-Heine-University, University Hospital, Düsseldorf, Germany
H. P. T. Ammon

⁷Department of Pharmacology, Institute of Pharmaceutical Sciences, University of Tübingen, Tübingen, Germany

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

Volltext

Referenzen

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
2 Castano L, Eisenbarth GS. Type-1 diabetes: A chronic autoimmune disease of human, mouse and rat. Annu Rev Immunol 1990; 8: 647-679
3 Lukic’ ML, Stosic-Grujicic’ S, Shahin A. Effector mechanisms in low-dose streptozotocin-induced diabetes. Dev Immunol 1998; 6: 119-128
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
5 Ammon HPT. Modulation of the immune system by Boswellia serrata extracts and boswellic acids. Phytomed 2010; 17: 862-867
6 Ammon HPT. Boswellic acids in chronic inflammatory diseases. Planta Med 2006; 72: 1100-1116
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
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
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
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
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
12 Lenzen S. The mechanism of alloxan- and streptozotocin induced diabetes. Diabetologia 2008; 51: 216-226
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
14 Schneider DA. Potential viral pathogenic mechanism in human type 1 diabetes. Diabetologia 2014; 57: 2009-2018
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
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
17 Fontbonne A. Markers of inflammation and prediction of diabetes mellitus in adults. Rev Epidemiol Sante Publique 1999; 47: 491-492
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
19 Melloul D. Role of NF-kappa B in beta-cell death. Biochem Soc Trans 2008; 36 (Pt 3) 334-339
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
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
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
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
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