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Garlic has an historical record for its use in medicine.

Effect of garlic on inflammation processes and atherosclerosis under human-like conditions in APOE*3-Leiden mice. Sonia M.S. Espirito Santo 1,2 , Wim van Duyvenvoorde 1 , Bart J.M. van Vlijmen 1,2 , Louis M. Havekes 1,2,3 and Hans M.G. Princen 1

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Garlic has an historical record for its use in medicine.

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  1. Effect of garlic on inflammation processes and atherosclerosis under human-like conditions in APOE*3-Leiden mice Sonia M.S. Espirito Santo1,2, Wim van Duyvenvoorde1, Bart J.M. van Vlijmen1,2, Louis M. Havekes1,2,3 and Hans M.G. Princen1 1TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands and 2Departments of Cardiology and 3Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.

  2. Garlic and health • Garlic has an historical record for its use in medicine. • Some studies have suggested that garlic significantly reduces plasma lipid levels, systolic and diastolic blood pressure and that it shows a strong antibiotic activity. Kik C, Kahane R, Gebhardt R. Nutr Metab Cardiovasc Dis. 2001;11:57-65. • In the last 15 years, garlic clinical trials and animal studies with well-characterized and standardized garlic material, with a consistent study design and dosage are poorly found.

  3. Possible effects of garlic on lipid metabolism LDL LIVER LDL receptor SYNTHESIS UPTAKE other receptors CHOLESTEROL STORAGE CHOLESTERYL ESTERS CONVERSION VLDL SECRETION BILE ACIDS BILIARY CHOLESTEROL BILE CHYLO- MICRON REMNANTS INTESTINE DIETARY CHOLESTEROL CHYLO- MICRONS

  4. Possible effects of garlic on atherosclerosis Shear stress Inflammation Oxidation Intima Fibrous cap Media Monocytes LDL Thrombus Endothelium oxLDL O2 Lipid core Collagen- degrading proteinases

  5. Contradictory effects attributed to garlic • Old human trials on healthy patients treated with garlic oil reported a decrease in plasma lipid levels. Bordia A, et al. Atherosclerosis.1975;21:15-19. Bordia A, et al. Prostaglandins, Leukotrienes and Essential Fatty Acids. 1998;58:257-263. • Recent human trials on hypercholesterolemic patients showed no effects of garlic powder (Kwai) and garlic oil treatment on plasma lipid levels. Simmons LA, et al. Atherosclerosis.1994;113:219-225. Berthold, et al. JAMA. 1998;279:1900-02. McCrindle BW, et al. Arch Pediatr Adolesc Med. 1998;152:1089-94. Isaacsohn JL, et al. Arch Intern Med.1998;158:1189-94. Gardner CD, et al. Atherosclerosis. 2001;154:213-220. Ziaei S, et al. Eur J Obstetrics & Gynecology. 2001;99:201-6. • Allicin showed no effects on plasma lipid levels and decreased aortic fatty streaks-like lesions in hypercholesterolemic C57Black/6 mice. D. Abramovitz et al., Coronary Artery Disease, 1999, 10: 515-519. • Induced-atherosclerosis in rabbits fed garlic oil and aged garlic extract (Kyolic) showed a decrease of aortic fatty streaks lesions. Bordia A, et al. 1980:428-37. Mand JK, et al. Indian Heart J. 1985;37:183-88. Efendy JL, et al. Atherosclerosis. 1997:132:37-42. Campbell JH, et al. J Nutr. 2001;131:1006S-09S. Durak I, et al. Nutr Metab Cardiovasc Dis. 2002 ;12:141-7. • Hypercholesterolemic pigs and rats fed garlic oil and garlic powder (Kwai) showed no benefical effects on atherosclerosis development. Heinle H,et al. Drug Res. 1994;44:614-17. Lee WM, et al. Exper Mol Pathol. 1980:33:345-8.

  6. Previous reported effects of garlic (LI111, Morado 200, Allicin and DADS) in APOE*3-Leiden mice • Lipid metabolism • No effects of garlic powders and isolated compounds on plasma lipid levels and markers of cholesterol synthesis and cholesterol absorption under hyperlipidemic conditions. • Morado 200 garlic powder showed an improved liver function, decreased plasma cholesterol levels and serum amyloid A levels under atherogenic conditions. • Fast atherosclerosis development • No decreasing effect of garlic on atherosclerosis of the aortic root was observed for all treatments. Espirito Santo SMS, et al. Effect of garlic powders and garlic isolated compounds on lipid metabolism. 2002.

  7. Effect of garlic on inflammation and atherosclerosis under human-like conditions: Aim Study the effect of 2 different doses of Printanor garlic powder • under mild human-like conditions • on inflammation related parameters • on atherosclerosis development by means of a hyperlipidemic and atherosclerosis-susceptible APOE*3-Leiden transgenic mice.

  8. APOE*3-Leiden transgenic mouse as a model for hyperlipidemia and atherosclerosis studies • Transgenic mice carrying a mutant form of human APOE*3 gene. • Dominant dysfunctional APOE*3-Leiden results in defect in chylomicron/ VLDL clearance and a more human-like lipoprotein profile. • Highly responsive to feeding cholesterol-rich diets. • Develops atherosclerosis varying from fatty streaks to more human-like complicated lesions.

  9. Atherosclerosis in APOE*3-Leiden mice Monocytes Adherence of monocytes to the activated vessel wall

  10. Atherosclerosis in APOE*3-Leiden mice Media not affected foam cells intima { media Aorta with regular fatty streak

  11. Atherosclerosis in APOE*3-Leiden mice cholesterol clefts necrosis fibrosis { intima media Affected media Severe plaque in aorta

  12. Effect of garlic on inflammation and atherosclerosis under human-like conditions: Garlic powders • Printanor FR 2001 (0.5% Prin): 0.5% of dry garlic powder with low sulphur content. • Printanor FR 2001 (5% Prin): 5% of dry garlic powder with high sulphur content. • Kyolic (positive control): 0.16% of dry garlic powder rich in S-allylcysteine reported to result in 64% reduction of fatty streaks in New Zealand white rabbits. Campbell JH, Efendy JL, et al. J.Nutrition. 2001;131:1006S-1009S.

  13. Effect of garlic on inflammation and atherosclerosis under human-like conditions: Experimental design 16 female APOE*3-Leiden mice per group 0.2% cholesterol diet for 24 weeks • General parameters: Body weight, food intake, marker of liver function, plasma lipid levels and blood pressure. • Inflammation related parameters: Serum amyloid A, soluble ICAM, Von Willebrand factor, fibrinogen, tissue-type plasminogen activator and whole blood stimulation assay. • Atherosclerosis related parameters: Aortic root lesions typing, total area, macrophage and smooth muscle cell lesions composition.

  14. Control Control Control Kyolic 0.5%Prin 5% Prin 6 Body weight gain (g) 4 * * 2 * * 0 0 4 8 12 16 20 24 0 4 8 12 16 20 0 4 8 12 16 20 Weeks Effect of garlic on body weight gain of APOE*3-Leiden mice P<0.01

  15. Control 0.5% Prin 5% Prin Kyolic Food intake (g/mouse/day) 2.76 ± 0.13 2.76 ± 0.10 2.73 ± 0.14 2.75 ± 0.12 Body temperature (C) 38.3 ± 0.2 38.3 ± 0.2 38.3 ± 0.2 38.3 ± 0.3 Effect of garlic on food intake and body temperature of APOE*3-Leiden mice

  16. Glucose Free fatty acids ( mM) ( mM) Control 10.1 ± 1.2 0.73 ± 0.13 0.5% Prin 9.4 ± 1.1 0.79 ± 0.11 * 5% Prin 9.7 ± 0.7 0.60 ± 0.10 * Kyolic 9.5 ± 1.1 0.62 ± 0.18 Effect of garlic on plasma free fatty acids and glucose levels of APOE*3-Leiden mice P<0.01

  17. 800 * 600 Total fat excretion (µmol/100g mouse/day) 400 200 0 Control 0.5% Prin 5% Prin Kyolic Effect of garlic on fecal fatty acids excretion of APOE*3-Leiden mice P<0.05

  18. Control Control Control Kyolic 0.5%Prin 5% Prin 150 100 Plasma ALAT levels (U/L) 50 0 0 4 8 12 16 20 0 4 8 12 16 20 0 4 8 12 16 20 Weeks Effect of garlic on liver function of APOE*3-Leiden mice

  19. Control Control Control Kyolic 0.5%Prin 5% Prin * 20 Cholesterol levels (mM) 15 10 5 0 0 4 8 12 16 20 0 4 8 12 16 20 0 4 8 12 16 20 Weeks Effect of garlic on plasma cholesterol levels of APOE*3-Leiden mice

  20. Control Control Control Kyolic 0.5%Prin 5% Prin 4 Triglycerides levels (mM) 3 2 1 0 0 4 8 12 16 20 0 4 8 12 16 20 0 4 8 12 16 20 Weeks Effect of garlic on plasma triglyceride levels of APOE*3-Leiden mice

  21. Before treatment with garlic preparations 2 Control 0.5% Prin 5% Prin Kyolic 1 0 0 8 16 24 0 8 16 24 0 8 16 24 0 8 16 24 mM After treatment with garlic preparations 2 1 0 0 8 16 24 0 8 16 24 0 8 16 24 0 8 16 24 Triglycerides Cholesterol Fractions Effect of garlic on lipoprotein profile of APOE*3-Leiden mice

  22. 12 weeks 16 weeks 160 120 Blood pressure (mmHg) 80 40 0 Control 0.5% 5% Kyolic Control 0.5% 5% Kyolic Prin Prin Prin Prin Effect of garlic on blood pressure of APOE*3-Leiden mice

  23. Conclusions After 20 weeks of mildly cholesterol elevating diets with incorporated garlic powders: • 5% Printanor treated group shows a significant (P=0.001) lower body weight, which coincides with: • a slight but significant lower plasma free fatty acids levels; • a significant higher fecal fatty acids excretion; • No effects of garlic on liver function, plasma lipid levels, plasma glucose levels and blood pressure were observed.

  24. Future perspectives • Focus on inflammation markers and atherosclerosis evaluation. • Follow up with a Human intervention study.

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