Effects of Garlic Extract Supplementation on Blood Lipid and Antioxidant Parameters and Atherosclerotic Plaque Formation Process in Cholesterol-Fed Rabbits

Effects of Garlic Extract Supplementationon Blood Lipid and Antioxidant Parameters

and Atherosclerotic Plaque FormationProcess in Cholesterol-Fed Rabbits

älker Durak, PhDH. Serdar Öztürk, MD, PhD

Ekmel Olcay, MDCengiz Güven, MD

ABSTRACT. Objective: Possible effects of garlic extract supplemen-tation on blood oxidant/antioxidant status, blood lipid profile and coro-nary plaque formation process were investigated in cholesterol-fed rabbits.

Methods: Thirty-one male rabbits of New Zealand strain were used.Twenty-two animals were given cholesterol for 4 months. Seven of themwere sacrificed to investigate plaque formation and to measure blood pa-rameters. Seven of the remaining 15 animals were fed on normal labora-tory diet and others normal diet plus garlic extract for additional 3months. Blood antioxidant and lipid parameters were measured andhistological examination was made.

Results: Total, HDL and LDL cholesterol levels were found to be sig-nificantly higher in the Cholesterol Group relative to controls. In thehistological investigation, a dense atherosclerotic plaque formation wasobserved in the aortas of this group. In the Normal Diet Group, total,HDL and LDL cholesterol levels were higher relative to the controlgroup. No significant differences were observed between plaque surface

älker Durak and H. Serdar Öztürk are affiliated with Ankara University MedicalFaculty, Department of Biochemistry, Ankara, Turkey.

Ekmel Olcay is affiliated with the Health Ministry Hifzisihha Institute, Departmentof Pharmacology.

Cengiz Güven is affiliated with Ankara University Medical Faculty, Department ofHistology and Embryology, Ankara, Turkey.

Address correspondence to: Prof. älker Durak, Ankara Üniversitesi Tip Fakültesi,Biyokimya ABD (Dekanlik Binasi), 06100 Sihhiye-Ankara, Turkey (E-mail: [email protected]).

Journal of Herbal Pharmacotherapy, Vol. 2(2) 2002 2002 by The Haworth Press, Inc. All rights reserved. 19

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areas of the Cholesterol and Normal Diet Groups. In the Extract Grouphowever, there were differences with regard to all the analysis parame-ters. Total, HDL and LDL cholesterol levels were found to be decreasedin this group. There was significant reduction in the plaque surface areain the aortas of this group. Blood antioxidant potential (AOP) was higherthan the other groups but, malondialdehyde (MDA) level and, value ofsusceptibility to oxidation (SO) were lower in the Extract Group relativeto the other groups. There were however no significant differences be-tween MDA and SO values of the Control and Extract Groups.

Conclusions: Our results demonstrate that cholesterol supplemen-tation leads to dense plaque formation in the aortas of the rabbits. Garlicextract supplementation ameliorates blood lipid profile and, increasesantioxidant potential. Extract treatment can significantly reduce plaquesurface area in the aorta. Our results suggest that increased blood antioxi-dant potential due to extract supplementation might be one of the factorsleading to this end. [Article copies available for a fee from The HaworthDocument Delivery Service: 1-800-HAWORTH. E-mail address: <[email protected]> Website: <http://www.HaworthPress.com> 2002 byThe Haworth Press, Inc. All rights reserved.]

KEYWORDS. Atherosclerosis, antioxidant system, antioxidants, gar-lic, rabbit

INTRODUCTION

Cardiovascular disease is the leading cause of mortality and morbid-ity in the world.1 Oxidation of cholesterol fractions, in particular LDL,has been accepted to play an important role in the atherosclerosis.2 Cho-lesterol, cholesterol esters and triglyceride components of the lipopro-tein fractions can be oxidized by toxic radicals and loss their chemicalstructures and cellular functions.3 Lipid peroxidation is accepted to be afree radical process implicated in the formation of atherosclerosis4 and,the aldehyde products of lipid hydroperoxide breakdown are responsiblefor the modification of LDL apoprotein.5 An increased concentration ofend products of lipid peroxidation is the evidence most frequentlyquoted for the involvement by toxic radicals in human diseases includ-ing atherosclerosis.6 The lipid-laden “foam cells” of atherosclerosis aremacrophages, which are known to produce oxygen radicals in theirmicrobicidal role.7 In atherosclerotic complications, macrophages areheld responsible for the oxidation of lipids and/or lipoproteins. It has

20 JOURNAL OF HERBAL PHARMACOTHERAPY

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http://www.HaworthPress.com

been argued that oxidized sterols produced by monocyte-macrophageslead to necrosis and progression of the atherosclerotic lesion.7,8

Although there are numerous studies to elucidate possible molecularmechanism(s) of atherosclerotic plaque formation process,9-13 no satis-factory explanations have been obtained yet. Furthermore, no success-ful non-invasive way has been found to eliminate previously formedatherosclerotic plaques. Therefore, researchers have performed intensestudies in order to avoid and/or eliminate atherosclerotic plaque forma-tion.

It is possible to find several studies on the antilipidemic,14-16 antioxi-dant,17-19 antiplatelet action,15,20,21 good haemostatic effects and haemo-dynamic properties22 of garlic, which is reported to be very rich in someorganosulfur compounds like alliin, allicin, diallyldisulfide, etc. Itshigh antioxidant potential is possibly resulted from these components.

Present study aims to investigate possible effects of garlic extractsupplementation on blood lipid parameters, blood antioxidant statusand atherosclerotic plaque formation process in cholesterol-fed rabbits.

METHODS

In this study, 40 male rabbits of New Zealand strain, being 10 in eachgroup were used. During the study period, 9 animals died from severalreasons were discarded. Therefore, remaining 31 animals were evalu-ated in the study. Of the rabbits aged 8-10 months and weighed 1900 ±100 g, 9 animals were used as control (Control Group). Twenty-two an-imals were given cholesterol (0.5 g/kg/day) for 4 months. At the end ofthis period, seven of them (Cholesterol Group) were sacrificed to inves-tigate atherosclerotic plaque formation and to measure blood lipid andantioxidant parameters. Remaining 15 animals were divided into twogroups. Seven were fed on normal laboratory diet (Normal Diet Group)and others (Extract Group) normal diet plus garlic extract (1.5 ml/kg/day)for additional 3 months. Cholesterol and extract were given by gastricintubation.

At each stage of the experimental period, blood samples were ob-tained from ear veins before animals were sacrificed. Biochemical anal-yses were performed in the serum samples within the same day. Aortasof the animals were removed (from origin to truncus coeliacus) and putin formaldehyde solution, 10% (v/v), for fixation. After 24 h, proximal

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part of the samples (0.5 cm) was cut across and embedded in paraffin.Paraffin sections of 5 µm thickness were stained with the standardhematoxyline-eosine stain. For the histological investigation, thesestained sections were used and their photographs were taken by aMC-80 Zeiss photomicroscope. Remaining part was dyed in Sudan IIIand then, photographs were directly taken from endothelial surfaces ofthese samples.

Cholesterol and triglyceride analyses and, liver and kidney functiontests were carried out in routine biochemistry laboratory. AOP, MDAand SO analyses in serum samples were made as described,23-25 respec-tively.

Aqueous garlic extract (Sarmex®) is prepared from a special kind ofgarlic (Kastamonu Garlic). For this aim, 2 kg of the garlic is incubatedin 10 L of water for one month and then aqueous part is removed to beused as the extract. The extract also includes sodium chloride (1% w/v).Antioxidant potential value of the extract measured with the methoddescribed23 is 596.4 nmol/ml?h, which is equivalent to the antioxidantpotential value of 980.2 mg ascorbic acid. It means that 1 ml extract isequivalent to approx. 0.980 g ascorbic acid on the base of their antioxi-dant potential values measured by the same method.23

Statistics: In the statistical analyses of the blood lipid and antioxidantparameters, One-way ANOVA and Tukey’s HSD procedures wereused. In comparison of the plaque surface areas Mann Whitney U testwas used. P values lower than 0.05 were accepted to be significant.

RESULTS

Results are given in Tables 1-4 and Figures 1-8. As seen from the re-sults, total, HDL and LDL cholesterol levels are highest in the Choles-terol Group. In the Normal Diet Group, total, HDL and LDL cholesterollevels are higher relative to control group. The values of the ExtractGroup are however similar to the Control Group. In this regard, total,HDL and LDL cholesterol levels are significantly lower in the ExtractGroup than those of the Cholesterol and Normal Diet Groups (Table 2).Moreover, HDL/total cholesterol ratios of the Control and ExtractGroups are similar but, those of Cholesterol and Normal Diet Groupsare lower than Control and Extract Groups (Table 3). HDL/LDL ratio ishighest in the Control Group. Although HDL/LDL ratio of the ExtractGroup is lower than that of the Control Group, it is significantly higher


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TABLE 1. Mean ± SD values of serum malondialdehyde (MDA) level, suscepti-bility to oxidation (SO) and antioxidant potential (AOP) in the groups.

Groups MDA (nmol/ml) SO (nmol/ml?min) AOP (nmol /ml?h)

I (n = 9) 13.77 ± 2.43 0.201 ± 0.085 20.82 ± 3.65

II (n = 7) 74.76 ± 22.92 1.108 ± 0.412 17.09 ± 3.32

III (n = 7) 39.29 ± 13.40 0.838 ± 0.298 19.76 ± 3.48

IV (n = 8) 19.68 ± 1.09 0.394 ± 0.065 27.20 ± 5.52

Statistical evaluation

ANOVA F = 35.97 P < 0.001 F = 21.83 P < 0.001 F = 8.26 P < 0.001

Tukey’s HSD procedure

I-II P < 0.01 P < 0.01 n.s.

I-III P < 0.01 P < 0.01 n.s.

I-IV n.s. n.s. P < 0.05

II-III P < 0.01 n.s. n.s.

II-IV P < 0.01 P < 0.01 P < 0.01

III-IV P < 0.05 P < 0.01 P < 0.01

n.s.: Non-significant (P > 0.05)I–Control Group, II–Cholesterol Group, III–Normal Diet Group, IV–Extract Group

TABLE 2. Mean ± SD values of serum total cholesterol (TC), triglyceride (TG),cholesterol fractions (HDL, LDL, VLDL), blood urea nitrogen (BUN) andcreatinine (CRE) levels (mg/dl) and, aspartate aminotransferase (AST) andalanine aminotransferase (ALT) activities (U/L) in the groups.

Groups TC TG HDL LDL VLDL AST ALT BUN CRE

I (n = 9) 50 ± 16 169 ± 27 20 ± 7 5.5 ± 2 33.5 ± 5.5 41 ± 3 93 ± 7 14.5 ± 2.5 1.7 ± 0.8

II (n = 7) 1350 ± 55 125 ± 20 228 ± 18 1098 ± 47 25 ± 4 43 ± 14 76 ± 18 15.7 ± 1.7 1.3 ± 0.9

III (n = 7) 1112 ± 270 162 ± 107 182 ± 46 905 ± 179 32.5 ± 9.4 48 ± 10 85 ± 16 19.1 ± 5.0 2.1 ± 0.9

IV (n = 8) 79 ± 22 95 ± 31 37 ± 9 22 ± 9 19 ± 4 42 ± 12 89 ± 14 16.2 ± 2.6 1.9 ± 0.8


ANOVA F = 208.2P < 0.001

F = 3.08P < 0.05

F = 143.7P < 0.001

F = 332.2P < 0.001

F = 10.29P < 0.001

F = 0.68n.s.

F = 2.04n.s.

F = 2.82n.s.

F = 1.12n.s.

Tukey’s HSD procedure (P values)

I-II 0.01 n.s. 0.01 0.01 0.05 n.s. n.s. n.s. n.s.

I-III 0.01 n.s. 0.01 0.01 n.s. n.s. n.s. n.s. n.s.

I-IV n.s. n.s. n.s. n.s. 0.01 n.s. n.s. n.s. n.s.

II-III 0.01 n.s. 0.01 0.01 n.s. n.s. n.s. n.s. n.s.

II-IV 0.01 n.s. 0.01 0.01 n.s. n.s. n.s. n.s. n.s.

III-IV 0.01 n.s. 0.01 0.01 0.01 n.s. n.s. n.s. n.s.

n.s.: Non-significant (P > 0.05)I–Control Group, II–Cholesterol Group, III–Normal Diet Group, IV–Extract Group

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than those of the Cholesterol and Normal Diet Groups (Table 3). As tothe weight gains of the animals, there were some differences betweengroups. In the first period (first 4 months), cholesterol-fed animalsgained more weight (gram) than control group (180 ± 23 vs. 145 ± 20,P < 0.001). In the second period (last 3 months), there were no signifi-


TABLE 3. Mean ± SD values of serum HDL/TC, LDL/TC and HDL/LDL ratios inthe groups.

Groups HDL/TC LDL/TC HDL/LDL

I (n = 9) 0.40 ± 0.13 0.11 ± 0.03 3.64 ± 1.30

II (n = 7) 0.17 ± 0.01 0.81 ± 0.04 0.21 ± 0.01

III (n = 7) 0.16 ± 0.04 0.81 ± 0.18 0.20 ± 0.04

IV (n = 8) 0.47 ± 0.12 0.28 ± 0.09 1.68 ± 0.52


ANOVA F = 114.87 P < 0.001 F = 102.4 P < 0.001 F = 92.74 P < 0.001

Tukey’s HSD procedure

I-II 0.01 0.01 0.01

I-III 0.01 0.01 0.01

I-IV 0.01 0.01 0.01

II-III n.s. n.s. n.s.

II-IV 0.01 0.01 0.01

III-IV 0.01 0.01 0.01

n.s.: Non-significant (P > 0.05)I–Control Group, II–Cholesterol Group, III–Normal Diet Group, IV–Extract GroupHDL: High density lipoprotein cholesterol, LDL: Low density lipoprotein cholesterol, TC: Total Cholesterol

TABLE 4. Mean ± SD values of plaque surface areas in the aortic tissues fromthe rabbits in the groups.

Groups Plaque surface area (%)

I (n = 9) -

II (n = 7) 75.2 ± 9.6

III (n = 7) 66.4 ± 9.2

IV (n = 8) 28.4 ± 7.3

Mann Whitney U test

II-III n.s.

II-IV P < 0.001

III-IV P < 0.001

n.s.: Non-significant (P > 0.05)

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FIGURE 1. Histologic section of a rabbit aorta from the Control Group. L: lu-men, M: tunica media, Thin arrow: internal elastic lamina. (3 100)

FIGURE 2a. Histologic section of a rabbit aorta from the Cholesterol Group. A:atherosclerotic plaques, L: lumen, M: tunica media, Thin arrow: internal elasticlamina. (3 25)

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cant differences between normal diet and extract groups concerning theweight gains (125 ± 21 vs. 132 ± 25, P > 0.05).

Blood antioxidant potential value of the Extract Group is signifi-cantly higher relative to the other groups but, MDA and SO values arelower in the Extract Group compared with those of the Cholesterol andNormal Diet Groups. MDA and SO values are, however, found to behighest in the Cholesterol Group.

With regard to liver and kidney function tests, no significant differ-ences were found between Control and other groups (Table 2). In thehistological examination, significant differences were observed be-tween groups. Photographs in Figures 4 and 8, which are taken from theaortas of the rabbits in the Extract Group seem of importance. As seenfrom the Figures 2a, 2b, 3, 6 and 7, there is a dense plaque formation inthe aortas of all the animals in the Cholesterol and Normal Diet Groups.However, there is significant reduction in plaque surface area in theaorta from the animals in the Extract Group (Table 4, Figures 4 and 8).


FIGURE 2b. Histologic section of a rabbit aorta from the Cholesterol Group. A:atherosclerotic plaques, L: lumen, M: tunica media, Thin arrow: internal elasticlamina, Thick arrow: foam cells in atherosclerotic plaques. (3 100)

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DISCUSSION

Natural remedies have been investigated for centuries for a wide va-riety of ailments. Among them, allium extracts have received special at-tention for their beneficial effects.26-31 However, there is no satisfactorydata from randomized controlled trials linking supplementation of thiskind of extracts including that of garlic in the diet with a reduction in thecardiovascular morbidity and mortality.32 Although significant reduc-tions in blood cholesterol and triglyceride levels were observed in somestudies when garlic extracts or powder was used, no good agreementhas been reached on this kind of clinical and experimental data sincemany of the trials suffered from significant methodological shortcom-ings including inappropriate methods of randomization, poorly charac-terized patient groups, short duration, insufficient statistical methods,etc.33

In spite of some diverse evaluations on the protective role of garlic inthe atherosclerotic diseases, it has long been suggested that garlic mayhave beneficial effects in atherosclerotic process.34-37 Although some

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FIGURE 3. Histologic section of a rabbit aorta from the Normal Diet Group. A:atherosclerotic plaques, L: lumen, M: tunica media, Thin arrow: internal elasticlamina. (3 50)

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unique properties of garlic like antioxidant and antilipidemic potentialshave been known,38-40 not much work has been conducted to investigatepossible effects of garlic on the relation between blood antioxidant pa-rameters and plaque formation process. The present study aims to eluci-date this subject and its relation to blood lipid profile and antioxidantstatus.

As seen from the results, garlic extract treatment can lower bloodcholesterol level and improve blood lipid profile, significantly. It also


FIGURE 4. Histologic section of a rabbit aorta from the Extract Group. L: lu-men, M: tunica media, Thin arrow: internal elastic lamina. (3 50)

FIGURE 5. Endothelial surface of the aorta from a rabbit in the Control Group.

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increases blood antioxidant potential, decreases MDA level, which isan important indicator of lipid peroxidation and, reduces susceptibilityof blood lipids to oxidation (Table 1). All these show that garlic extracthas high antioxidant potential in vivo as well and, protects cellularstructures against peroxidation. Since oxidation of cholesterol frac-tions, in particular LDL, has been accepted to play an important role inthe atherosclerotic plaque formation process2 and, lipid peroxidation isa radical process implicated in this formation,4 it has been proposed thatextracts rich in antioxidant content like that of garlic may give benefi-cial results in this regard. It is quite possible that high antioxidant and

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FIGURE 6. Endothelial surface of the aorta from a rabbit in the CholesterolGroup. Note bright-red atherosclerotic plaques (Sudan III stained).

FIGURE 7. Endothelial surface of the aorta from a rabbit in the Normal DietGroup. Note bright-red atherosclerotic plaques (Sudan III stained).

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redox potential of the garlic extract can re-reduce oxidized chemicalstructures in the outer layer of the coronary plaques (which are thoughtto be responsible chemical structures for the plaque formation processin the coronary arteries). We think that these reduced chemical groupscan then be progressively removed from endothelial surface since theyare being soluble in the blood after reduction reactions. In addition to itscholesterol lowering property, we think that above mentioned chemicalevents might play part in the elimination of the coronary plaques.

Results suggest that activated antioxidant system due to garlic extractsupplementation may play part in the reduction of plaque surface area.However, other possible molecular mechanisms need to be investigatedfurther before reaching a final decision on the subject.

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FIGURE 8. Endothelial surface of the aorta from a rabbit in the Extract Group.

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SUBMITTED: 04/25/01REVISED: 06/20/01

ACCEPTED: 08/01/01


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