INTRODUCTION:

Garlic has played an important dietary and medicinal role throughout the history of mankind. Garlic is a nature’s boon to mankind. For over 5000 years garlic has been consumed both as food and used for medicine by ancient scholars. Garlic, Allium sativum L. is a member of the Alliaceae family, has been widely recognized as a valuable spice and a popular remedy for various ailments and physiological disorders. The name garlic may have originated from the Celtic word 'all' meaning pungent. As one of the earliest cultivated plants, garlic is mentioned in the Bible and in the literature of Ancient Israel (The Talmud), Egypt (Codex Ebers) and India (Vedas and Purans, Charak Sanghita).Chinese strongly believe that garlic prolongs longevity and is useful in treating most human diseases, including infections, cancer and heart diseases. In historical writings of India and in literature like Vedas and Purans, garlic is reported to have medicinal as well as nutritive value in food items. Clinical indications of garlic include hemorrhoids, rheumatism, dermatitis, abdominal pain, cough,loss of appetite and loss of weight.

The medicinal qualities of garlic were described by Pliny the Elder, Aristophanes, and Galen. Hippocrates, the Father of Medicine, observed that garlic was excellent for curing tumors and is an effective diuretic. Aristotle attributed garlic as a cure for rabies, and the Prophet Mohammad recommended it for treating scorpion stings. In Historia Naturalis by Pliny, garlic was recommended for gastro-intestinal disorders as well as dog and snake bites. Desired medicinal results of garlic are obtained when bulbs are chewed and swallowed or mixed with food and eaten.

Preparations of garlic are available as tablets, capsules, syrup, tinctures and oil. In ointment form, garlic has been used externally for treatment of ring worm; boiled with vinegar and sugar for treatment of asthma; made into an infusion for treatment of epilepsy; pounded with honey for use against rheumatism; and mixed with milk for use as a vermifuge. Garlic is commonly used in Europe and Asia for medicinal benefits in healing wounds, etc.In Germany, sale of garlic preparations competes with sales of leading drugs.Garlic produces a variety of volatile sulfur-based compounds which are effective as insect repellents and insecticides. Diallyl disulfide is one of such compounds which has a strong odor and acts as a powerful insecticide.Commercial preparations of garlic are certified as insecticide against mites, nematodes and mosquito larvae affecting a variety of crops.

It has been used as a medicinal agent for thousands of years. It is a remarkable plant, which has multiple beneficial effects such as;

Diabetes mellitus:

Garlic use may be associated withincreased serum insulin and improved liver glycogen storage.A constituent of garlic, allylpropyl disulfide, may reduce bloodglucose and increase insulin. Hypoglycemic effect of garlic in human is not well studied. Chronic feeding of garlic oil and garlic powder showed significant decrease in blood glucose level whereas some other studies showed no change of blood glucose level. All human studies, except one or two, showing effect of garlic on blood glucose level on normal healthy individuals but not in diabetic patients. Thus the role of garlic in diabetic condition is yet to be confirmed.

Though the exact mechanism/s of garlic as antidiabetic agent is still not clear but in-vivo as well as in-vitro studies showed that garlic acts as an insulin secretagogue in diabetic rats. Augusti and Sheela also proposed that antioxidant effect of S-allyl cysteine sulfoxide (isolated product from garlic) may also contribute for its beneficial effect in diabetes .Another proposed mechanism is due to spare insulin from sulphydryl group. Inactivation of insulin by sulphydryl group is a common phenomenon. Garlic (allicin) can effectively combine with compounds like cysteine and enhance serum insulin. Jain and Vyas proposed that garlic can act as an antidiabetic agent by increasing either the pancreatic secretion of insulin from the beta cells or its release from bound insulin¹.

Hypocholesterolaemic activity:

Intake of high-fat meals causes a significant increase in serum triglyceride and cholesterol levels. Observations suggest that use of garlic (and onion as well) prevents the hypercholesterolemia induced by high-fat meal. Eating of 10 g fresh garlic per day for 2 months significantly decreases (15%-28.5%) serum cholesterol levels among hypercholesterolemic patient. Sainani et al. (1979) compared vegetarians, with different eating habits with regards to the use of onions and garlic.Group I consumed onion and garlic in liberal amounts (50 g garlic and 600 g onion per week); Group II consumed small amount of onion and garlic (10 g garlic and 200 g onion per week), and Group III totally abstained from the use of garlic and onion.

The level of cholesterol, triglyceride, phospholipids and ß- lipoproteins were the lowest in the individuals consuming liberal amounts of garlic and onion.Total serum cholesterol is an important factor in the development of ischemic heart disease (IHD). Cholesterol present in the ß-lipoprotein (LDL, Low density lipoprotein) and pre-ß-lipoprotein (VLDL, Very low density lipoprotein) fractions finds its way into the arterial wall, whereas ß-lipoprotein (HDL, High density lipoprotein) cholesterol helps to reduce the serum cholesterol level. Increase in HDL/LDL ratio is a preventive effect of the development of IHD. Jain (1977) and Bordia (1981) observed that consumption of 0.25 mg/kg garlic oil caused a steady decrease in LDL+VLDL levels with concomitant increase in HDL levels. Aged garlic extract, aqueous extract from garlic powder, and its constituents lower serum cholesterol level and inhibit the oxidative modification of LDL, and thus is presumed to have a protective effect against atherosclerosis. The multiple inhibitory effects of garlic extracts at several different steps in cholesterol biosynthesis pathway in human Hep G2 cells. Compounds (allicin) present in water soluble extracts of garlic inhibit the biosynthesis of cholesterol in hepatocytes,thus contributing to the reduction of serum cholesterol. Garlic derived components are capable of combining with the sulphydryl (-SH) group. Reduced conversion of acetate into cholesterol has been observed both in vivo and in vitro. As -SH groups are involved in several metabolic pathways, it may be inferred that garlic besides inhibiting lipid synthesis would affect other metabolic activities as well. Tellurium compounds found in high concentration in fresh garlic bulb may contribute to hypocholesterolaemic action by inhibiting squalene epoxidase, the penultimate enzyme in the synthetic pathway of cholesterol. Oxidation of LDL plays an important role in the initiation and progression of atherosclerosis².

Anticancer activity:

Cancer, the second major killer in Western countries, results from DNA mutations, that accumulate over time, increasing risk with age. Free radical injury and chemical carcinogen-binding are major causes of DNA damage³. Garlic-rich diets have been shown to lower the risk of human stomach, colon and prostate cancer⁴.

Garlic is one of the most ancient spice plants reputed to have an effect on cancer. As recorded around 1550 B.C. in the Ebers Papyrus, garlic was applied externally for the treatment of tumors by ancient Egyptians and internally by Hippocrates and Indian physicians. China provides an ideal “Field Laboratory” for epidemiological studies of cancer incidence.Stomach cancer was found to rank higher for males and females in cancer mortality than other cancer incidence in China They suggested that consumption of garlic may have inhibited nitrate reduction by bacteria. Subsequently, the lower gastric nitrite (a nitrosamine precursor) concentration may reduce the risk of developing stomach cancer. Cigarette smoking, use of salty foods and moldy grains are associated with increased risk of stomach cancer. A significant reduction of stomach cancer risk was found to be associated with increasing consumption of garlic, scallicens and Chinese chives. Galeone et al. investigated the role of allium’s vegetables in the etiology of various neoplasms. They analyzed the relation between frequency of onion and garlic use and cancer at several sites of Italian and Swiss case control studies. They reported an inverse relationship between the frequency of use of garlic and the risk of several common cancers. Natural killer-cells of raw garlic and aged group destroyed 139% and 159% more tumor cells than those from the control group. Aged garlic extract is a good chemopreventive agent for colorectal cancer. Aged garlic extract could prevent tumour formation by inhibiting angiogenesis through suppression of endothelial cell mortality,proliferation and tube formation.Aflatoxins are naturally occurring toxic metabolites produced by Aspergillus flavus and related fungi. Among the 16 or more toxic compounds secreted by these fungi, aflatoxin B1 (AFB1) is most potent in causing mutations in various microorganisms as well as mammalian and human cells. It is both toxic and hepato-carcinogenic to a variety of animals and humans in Asia and Africa. Two organosulfur compounds of garlic, ajoene and dially sulfide affected AFB1 metabolism and DNA binding by inhibiting phase I enzymes and, therefore, act as potential cancer chemopreventive agents.

Garlic is one of the best natural sources of germanium which has also been reported to prevent and cure cancer. Garlic is also an excellent source of selenium, which has potential therapeutic value in cancer treatment. Semethylselenocysteine is the major seleno-compound in garlic bulb. Epidemiological studies have indicated a negative relationship between selenium intake and the incidence of certain cancers. Blood or plasma levels of selenium are usually lower in patients with cancer than those without this disorder. In mammary tumor model, se-methyl selenocysteine was shown to be most effective seleno-compound so far in reduction of tumors.

A potential carcinogen may exert its effects by producing nuclear damage. The effect of a sulfide and disulfide component of garlic on several chemical carcinogens. DMH (1,2-dimethyhydrazine) and NMBA (N-nitrosomethyl benzylamine) are procarcinogens, which are metabolized in the liver to carcinogenic metabolites, an effect mediated by their binding to the nucleus. Pre-administration of diallyl sulfide prevented nuclear damage induced by DMH and NMBA. These observations suggest that diallyl sulfide might inhibit the conversion of procarcinogens to ultimate carcinogens, an important factor of the initiation phase of carcinogenesis. Garlic juice reduced endogenous formation of carcinogens N-nitrosodimethylamine (NDMA) in young human. Recently,it have reported that consumption of garlic powder induced a 35-60% reduction in DNA damage induced by NDMA in rat.Glutathione-s-transferase (GST) is an important enzyme that conjugates electrophils and assists in the detoxification of many carcinogens. Compounds that increase GST activity have been found to inhibit carcinogen induced neoplasia.Oral administration of methyl trisulfide and diallyl disulfide stimulated glutathione-s-transferase activity, which increased with time and showed a time lag of 18 h or more.These studies suggest that stimulation of glutathione-s-transferase activity in the liver and other target organs of carcinogens by garlic derived organosulphur compounds may be responsible for their protective effects in chemical carcinogenesis and on different stages of carcinogenesis.

Oxygen radicals may play a role in tumor promotion. Various anti-oxidants, trace radicals, scavengers, stimulation of super oxide dismutase, glutathine peroxidase inhibitors of cyclooxigenase and lipooxygenase enzymes were found to modulate the oxidative stress and the formation of molecular species involved in tumor promotion. Garlic oil stimulated glutathione peroxidase activity, and inhibited the decrease in the intracellular ratio of reduced to oxidize glutathione produced by TPA in epidermal cells. Garlic oil was also found to inhibit lipooxigenase enzymes, which is involved in TPA-stimulated arachidonic acid metabolism. The effect of aged garlic extract (AGE) and two of its components, s-allylcysteine (SAC) and s-allyl mercaptocysteine (SAMC), on human breast cancer cells MCF-7 and MCF-7-s. They observed an anti-proliferative response to SAC and SAMC and an alteration in glutathione level without significant concurrent changes in the glutathione metabolizing enzymes. SAMC exerts anti proliferative effects by binding directly to tubulin and disrupting the microtubule assembly, thus arresting cells in mitosis and triggering JNK1 and caspase-3 signaling pathways that lead to apoptosis. Xu et al. (2004) reported a novel aspect into the understanding of the molecular mechanism of potential antitumor action of ajoene. Ajoene-treated leukemia cell line HL60 cells were arrested in G(2)/M phase and total amount of cytosolic proteasome increased. Proteasome plays a key role in the regulation of many cellular processes. Allicin inhibited the growth of cancer cells of murine and human origin. Allicin induced the formation of apoptotic bodies, nuclear condensation and a typical DNA ladder in cancer cells. Allicin activate the caspases-3,-8 and –9 and cleavage of poly (ADP-ribose) polymerase. Diallyl trisulfide found in garlic bulb induces apoptosis in PC-3 human prostate cancer cell by induction of protein Bax and Bak. Chu et al. (2006) studied the effect of garlic derivatives S-allylcysteine and S-allylmercaptocysteine on the inhibition of cancer cell invasion through restoration of E-cadherin expression. They suggest that these compounds might be potential therapeutic agents for suppressing androgen-independent prostate cancer.It seems that garlic derived organosulfur compounds could have effects on different stages of carcinogenesis. It is now recognized that a wide range of human cancer, perhaps as many as 80-90% is attributed to environmental factors. Garlic has been shown to inhibit growth of transplantable tumors and to reduce the incidence of certain spontaneously occurring tumors.Components of garlic also inhibit the activity of diverse chemical carcinogens during both the initiation and promotion phases of carcinogenesis.

Kodera et al. (1989) isolated a new allixin (phytoalexin) synthesized by garlic. Being a phenolic compound, it is an effective inhibitor of phospholipid metabolism stimulated in vitro by the tumor promoter. Allixin plays an important role in cancer prevention. Allicin exhibits immune-stimulatory and antitumor properties. Immune stimulatory effect of allicin is mediated by redox-sensitive signaling such as activation of p2(ras). The antitumor effect of allicin is related to its immune-stimulatory properties.Allicin inhibits the apoptosis of macrophages in depleted nutritional state through the mitogen-activated protein kinase/extra cellular signal-regulated kinase pathway .Diallyl disulfide (DADS) found in garlic bulb inhibits colon tumor cell proliferation.They suggest that 200 M of DADS increases histone acetylation, CDKN1A mRNA and p21 (waf1)protein levels and induces G2/M cells cycle arrest in tumor cells. Pretreatment of rats with 50-100 mg garlic oil/kg body weight for a week significantly protects free radical injury and cancer in kidneys induced by ferric nitrilotriacetate (Fe-NTA). This is due to the inhibition of hepatic tumour markers viz., ornithine decarboxylase activity and DNA synthesis. It is therefore obvious that the organosulphur compounds of garlic extend their protective anti-cancer effects in three ways: (i) a direct inhibition of tumor cell metabolism; (ii) inhibition of the initiation and/or promotion phases of carcinogenesis; and (iii) modulation of the host response by augmenting macrophages and T-lymphocytes function¹⁵.

Experimental gastric carcinoma and precancerous lesion were associated with hypocholesterolaemia, LDL and HDL. Garlic and garlic-green tea mixture can inhibit and reverse MNNG-induced gastric carcinoma and precancerous lesion in Wistar rats⁵.

The herbal supplement garlic (Allium sativum) is commonlyused by cancer patients. Preclinical studies have shown thatallicin, a major component of garlic, may affect cytochromeP450 3A4 (CYP3A4) activity. This study examines the influenceof garlic supplementation on the pharmacokinetics of docetaxel,a CYP3A4 substrate. Women with metastatic breast cancer weretreated with docetaxel (30 mg/m²) given weekly for 3 of 4 weeks.Three days after the initial dose of docetaxel, patients received600 mg of garlic twice daily for 12 consecutive days. Docetaxelpharmacokinetics were assessed during the first three administrations⁶.

Some organosulfur compounds derived from garlic, including S-allylcysteine, have been found to retard the growth of chemically induced and transplantable tumors in several animal models. Therefore, the consumption of garlic may provide some kind of protection from cancer development⁷.

The gastric cancer cell lines MGC-803 and SGC-7901 were treated with allicin. Proliferation inhibitory rate was detected by trypan-blue exclusion. Morphologic changes were observed by electron microscopy. The cell cycle was examined by flow cytometry and Giemsa staining. Expression of p21WAF1, p16INK4 protein and mRNA was detected by immunohistochemistry and RT-PCR. The gastric cancer cells were inhibited after exposure to allicin for 24 hr, The IC50 was 6.4 microg/ ml in MGC-803 cells and 7.3 microg/ml in SGC-7901cells. After exposure to allicin of 12 microg/ml for 24 hr, it caused the cytotoxic effect on the cells, including cellular membrane breakage. After exposure to allicin of 3 microg/ml, 6 microg/ml and 9 microg/ml for 24 hr, compared with the control group, the proportion of cells in the G0/G1 phase was decreased and that in the G2/M phase was increased significantly. After exposure to allicin of 6 microg/ml for 24 hr, compared with the control group, cell division index was much higher, suggesting that allicin could induce cell arrest in M phase. Allicin induce cell arrest of gastric cancer in M phase, which may be related to the up-regulated expression of p21WAF1 and p16INK4 genes. garlic allicin heart⁸.

Garlic can detoxify carcinogens by stimulation of cytochrome P(450) enzymes, antioxidant activity or sulfur compound binding. Studies demonstrate a direct toxic effect of garlic to sarcoma and gastric, colon, bladder and prostate cancer cells in tissue culture, but these effects cannot explain the inhibition of growth of transplanted cancer in animal models. The most likely explanation of this effect is immune stimulation. Comparison of the effects of garlic to BCG immunotherapy reveals many similarities. Both stimulate proliferation of lymphocytes and macrophage phagocytosis, induce the infiltration of macrophages and lymphocytes in transplanted tumors, induce splenic hypertrophy, stimulate release of interleukin-2, tumor necrosis factor-alpha and interferon-gamma, enhance natural killer cell, killer cell and lymphokine-activated killer cell activity. These activities represent effective stimulation of the immune response. Studies suggest that garlic may be useful in preventing the suppression of immune response that is associated with increased risk of malignancy. Data suggest that maintenance of immune stimulation can significantly reduce the risk of cancer. Clinical trials should be initiated to test the hypothesis that the immune stimulation and other beneficial effects of garlic are able to reduce the incidence of cancer⁹.

Garlic organosulfur compounds exert chemopreventive effects at several organ sites in rodents after administration of chemical carcinogens, possibly by inhibiting carcinogen activation via cytochrome P-450-mediated oxidative metabolism. The variability in potency of tumor inhibition by garlic sulfur compounds is due to structural differences, such as the number of allyl and sulfur groups. In this study, diallyl sulfide (DAS), diallyl disulfide (DADS), and allyl methyl sulfide (AMS) were administered to acetone-treated adult male Sprague-Dawley rats by gastric gavage at a dose of 1.75 mmol/kg in cottonseed oil. After 15 hours, hepatic microsomal cytochrome P-450 activity and content were examined. The activity of p-nitrophenol (pNP) hydroxylase (E.C. 1.14.13.29) was significantly decreased by all garlic compounds, whereas benzphetamine N-demethylase and ethoxyresorufin O-deethylase activities were not changed. The activity of pNP hydroxylase was decreased to 31%, 54%, and 65% of control activity, and immunodetectable CYP2E1 protein levels were decreased in a similar manner by DAS, DADS, and AMS, respectively. Additional acetone-treated rats were given 4-methyl pyrazole, a ligand specific for CYP2E1, intraperitoneally five hours after garlic compound administration. Ten hours later, pNP hydroxylase activity was decreased to 73%, 78%, and 67% of control levels by DAS, DADS, and AMS, respectively. Further studies are needed to determine whether the variable potency of inhibition of CYP2E1 enzyme activity is related to chemopreventive efficacy of garlic sulfur compounds¹⁰.

Allyl sulfur compounds play a major role in the chemoprevention against carcinogenesis. The present study compared the antiproliferative effects of diallyl sulfide (DAS), diallyl disulfide (DADS) and garlic extract on p53-wild type H460 and p53-null type H1299 non small cell lung cancer cells (NSCLC). The DAS and DADS treatment of both H460 and H1299 cells resulted in the highest numbers of cells in apoptotic state as measured by acridine orange staining, however, garlic extract treatment did not induce any significant apoptotic cells by MTT assay. A DAD was found to be more effective in inducing apoptosis on NSCLC. The level of p53 protein in H460 cell was increased following DADS treatment. DAS and garlic extract treatment of H460 cells induced a rise in the level of Bax and a fall of Bcl-2 level. These results demonstrate that DAS, DADS and garlic extract are effective in reduction of anti-proliperative gene in NSCLC and suggest that modulation of apoptosis-associated cellular proteins by DAS, DADS and garlic extract may be the mechanism for apoptosis which merit further investigation as potential chemoprevention agents¹¹.

Antimicrobial activity:

Garlic juice diluted to one part in 125,000 inhibits the bacterial growth of Staphylococcus, Streptococcus,Vibrio (including V. cholerae) and Bacillus (including Bacillus typhosus, B. dysenteriae and B. enteritidis). 10 % extract of dehydrated garlic bulb demonstrated antibactericidal action against Salmonella typhimurium and Escherichia coli within 2 to 6 h exposure.Crude extract of garlic has proven to be quite effective against both gram-negative and gram-positive bacteria. Bacterial cultures resistant to the commonly used antibiotic chloramphenicol appear sensitive to garlic. Preparation of fresh garlic and vacuum dried powdered garlic preparations were effective against Staphylococcus aureus, Streptococcus viridans, Streptococcus haematyticus, Klebsiella pneumoniae, Proteus vulgaris, Escherichia coli, Salmonella enteritidis, Bacillus subtilis, B. megaterium, B. pumitus, B. mycoides, B. thuringiensis,Sarcina lutea, and Serratia marcescens.Heating, storage and ultraviolet exposure of fresh garlic juice significantly inhibited its antimicrobial activity against common human pathogens. Allicin, methyl allylthiosulfinates and allylmethylsulfinates, constituents in aqueous garlic clove and powder homogenate, had in vitro antibacterial activities while polar compound alliin did not. Allicin and allyl-methyl plus methyl-allylthiosulfinate have shown inhibition of the in vitro growth of Helicobacter pylori, the bacterium responsible for serious gastric diseases as ulcer and even gastric cancer.Sasaki and Kita (2003) reported the antibacterial activity of garlic powder against Bacillus anthracis. A 1% water solution of garlic powder in the test tube method killed B. anthracis within 3 h of treatment at room temperature. Garlic extract inhibits the growth of oral pathogens and certain proteases and thus it may have therapeutic value, particularly for periodontitis².

The MIC of chlorhexidine for the 28 MDR and 28 non-MDR of S. mutans varied from 4 to 16 mg/ml and 0.25 to 1 mg/ml, respectively. The inhibitory effect of garlic extract on 28 MDR strains of S. mutans revealed. The diameter of the zones of inhibition around the disks varied from 22 to 44 mm, indicating that all 28 MDR isolates (100%) were sensitive to garlic extract. The MIC of garlic extract for the 28 MDR and 28 non-MDR strains of S. mutans as measured by broth dilution method ranged from 4 to 32 mg/ml (approximately 16-128 mg/ml allicin) among which 25 (90%) showed garlic MIC = 16 mg/ml¹².

The antimicrobial effects of aqueous garlic extract (AGE) against 133 multidrug-resistant gram-positive and gram-negative bacterial isolates, including Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Salmonella typhi, Pseudomonas aeruginosa, Escherichia coli, Shigella spp., and Proteus spp., and against 10 Candida spp. were studied. Antibacterial activity of AGE by well-diffusion and macrobroth dilution method was characterized by inhibition zones of 20.2-22.7 mm for gram-positives and 19.8-24.5 mm for gram-negatives and minimum inhibitory concentration (MIC) ranges of 15.6-48.3 mg/mL and 22.9-37.2 mg/mL, respectively. With the exception of P. aeruginosa, the observed disparity in MIC values at 24 and 48 hours was not significant (P >.05) in these isolates. The anticandidal effect of AGE resulted in a growth inhibition zone of 27.4 +/- 3.7 mm with no significant difference (P >.05) in MIC values at 24 and 48 hours, respectively. Minimum fungicidal concentrations were found to be 14.9 and 15.5 mg/mL, respectively, at these incubation periods. Further analysis revealed the antimicrobial efficacy of AGE to be dose and time dependent, producing five distinct time-kill profiles among the isolates tested. The results of this study support the use of garlic in health products and herbal remedies in Nigeria¹³.

Six different mixtures of garlic distilled oils containing diallyl disulfide (DDS) and diallyl trisulfide (DTS), ranging from 1 to 51% and 88 to 38% respectively, have been assayed against a number of yeasts (C. albicans, C. tropicalis and B. capitatus), gram-positive bacteria (S. aureus and B. subtilis) and gram-negative bacteria (P. aeruginosa and E. coli). Results obtained support a specific antifungal more than an antibacterial activity and implicate DDS as the active constituent. Incubation of garlic extracts made up of 1% DDS and 88% DTS resulted, in fact, in the absence of growth inhibition against all the tested microorganisms, whereas garlic oils with higher quantities of DDS showed significant inhibitory activity, increasing with the increase of DDS amount¹⁴.

A broad range of bacteria, including E. coli, Staphylococcus Aureus, Streptococcus pyogenes, Proteus mirabilis, Pseudomonas aeruginosa, Acetobacter baumanii, Klebsiella pneumoniae, Enterococcus faecium, Myco-bacterium tuberculosis, H. pylori, Salmonella, Clostridium and Shigella are allicin-sensitive.

Some of the bacteria listed are killed by allicin concentrations as low as 3-15 ppm (3-15 mcg/ml).5 Fortunately, friendly bacteria such as Lactobacillus, Enterococcus and Pediococcus are fairly resistant to allicin.1,9 They also note that allicin synergizes with antibiotics, and that most bacteria are unable to develop resistance to allicin.5 They also report from their own research that various multi-drug resistant bacteria are also effectively killed by allicin, some at doses as low as 15-30 ppm (15-30 mcg/ml)¹⁵.

Numerous test tube studies have demonstrated that garlic extract inhibits the growth of different species of bacteria, including Mycobacterium tuberculosis, the organism responsible for tuberculosis. However, very high concentrations of garlic extract were needed to slow down the growth of M. tuberculosis in these studies, so some experts are concerned that these levels may be toxic to people. While further research in people is needed, one animal study found that garlic oil (which is a higher concentration than the extract) also inhibited M. tuberculosis and reduced the tuberculosis lesions in the lungs of these animals. Some scientists speculate that a combination of garlic extract or garlic oil with anti-tuberculosis drugs may eventually prove effective against the disease. Research to test this theory is needed.

AGE enhances macrophage and spleen cell activity, improves the ratio of helper/suppressor cells in AIDS patients, increases the activity of natural killer cells (NK), that kill invading organisms and cancer cells, stimulates T lymphocyte proliferation, increases lymphocyte toxicity against cancer cells and boosts activity of phagocytic cells.^16-18

In a clinical study, subjects ingesting 1 800 mg of AGE/day for 3 weeks, showed a 155.5% increase in NK cell activity, while those receiving 35 grams of fresh garlic/day (equivalent to 10 cloves) had only a 139.9% increase, indicating the superior immune-enhancing benefit of AGE.18 In another study, with AIDS patients, NK cells, that are depleted in AIDS, rose to normal levels after receiving AGE supplement for 6 weeks.¹⁹

Antioxidant activity:

Damage to DNA, lipids and proteins, by ROS, leads to disease and aging, as ROS damage induces cancer-causing mutations, disrupt enzymes, injure membranes and reduce immunity. ROS, that are by-products of normal metabolism, are normally neutralized by cellular antioxidant enzymes and small molecules, such as glutathione and by vitamins, minerals and phytochemicals, obtained in the diet. Increased levels of ROS, in inflammation and during exposure to sunlight, ionising radiation, pollutants, exercise and some medications, requires additional antioxidant protection and in its absence oxidative stress occurs. Oxidative stress plays a role in arthritis, atherosclerosis, heart disease, stroke, AIDS, cancer, ageing, and in programmed cell death (apoptosis) of neurons, that leads to Alzheimer’s disease and other neurodegenrative conditions.^33,34. AGE is richer in antioxidants than other commercial garlic preparations and fresh garlic^20-24and it also boosts cellular antioxidants, including glutathione, that helps maintain a healthy immune system and prevents drug toxicity, and peroxidases that eliminate toxic peroxides.²⁵

Some components of garlic have tremendous antioxidant properties, including the ability to scavenge free radicals, increase the activity of several antioxidant enzymes in the body (superoxide dismutase, catalase, glutathione peroxidase, and glutathione), inhibit lipid peroxidation, and block inflammatory prostaglandins.Raw garlic homogenate augmented endogenous antioxidants along with reduction of basal lipid peroxidation in rat heart, liver and kidney in a dose dependent manner. Aged garlic extract (AGE) also exerted its antioxidant action by scavenging reactive oxygen species and enhancing the cellular antioxidants, like reduced glutathione superoxide dismutase, catalase and glutathione peroxidase of vascular endothelial cells. Augmented endogenous antioxidants on heart and endothelial cells have important direct cytoprotective effects, especially in the event of oxidant stress induced injury. Chronic oral administration of garlic homogenate protected the rat heart from in vitro ischemic reperfusion injury and oxidative stress induced by single dose of adriamycin. AGE has been shown to offer protection against the cardiotoxic effects of doxorubicin, an antineoplastic agent used in cancer therapy .Feeding of garlic powder in rats for 11 days had a protective effect on isoproterenol-induced myocardial damage. In another study, the size of the ischemic zone was significantly reduced and the onset of arrhythmia after occlusion of the descending branch of the left coronary artery was significantly prolonged in rats fed with a standard chow enriched with 1% garlic powder for 10 weeks.Aqueous garlic extract was also found to be effective in reducing Cu (+)-initiated oxidation of low density lipoprotein (LDL) as measured by photochemiluminescence method.AGE also protected vascular endothelial cells from H₂O₂-induced oxidant injury²⁶ .

The antioxidant properties of some isolated garlic compounds also have been studied. Allicin, the main component in aqueous extract from raw garlic and garlic powder, scavenges hydroxyl radicals and inhibit lipid peroxidation and prevents the lung damage induced by ischemia-reperfusion .The antioxidant properties of allicin may explain, at least in part, the ability of these extracts (from raw garlic or garlic powder) to inhibit Cu²⁺-induced lipoprotein oxidation in human serum. Alliin, the main component in extracts from boiled garlic cloves, microwave-treated garlic cloves and pickled garlic, scavenges hydroxyl radicals, hydrogen peroxide, and inhibits lipid peroxidation and LDL oxidation. This may explain, at least in part, the ability of boiled garlic, microwave-treated garlic, or picked garlic to inhibit Cu²⁺-induced lipoprotein oxidation in human serum. Interestingly, it has been shown that another garlic compounds such as S-allylcysteine, N-acetyl-S-allylcysteine , S-allylmercaptocysteine, alliin, allixin, S-ethylcysteine, N-acetylcysteine, diallyl sulfide, and diallyl disulfide are able to inhibit Cu²⁺-induced LDL oxidation. The antioxidant properties of S-allylcysteine ,S-allylmercaptocysteine,diallyl sulfide , and diallyl disulfide also have been seen in vivo in an experimental model of nephrotoxicity induced by gentamicin. The ability of garlic to prevent Cu²⁺-induced lipoprotein oxidation in human serum is preserved in spite of inactivation of allinase by boiling, microwave or pickling or by the heating of garlic extracts and that the compound(s) involved in the inhibition of Cu²⁺-induced lipoprotein oxidation are heat stable. The garlic extracts used in our study were unable to chelate Cu²⁺suggesting that the ability of these extracts to inhibit Cu²⁺-induced lipoprotein oxidation is not secondary to Cu²⁺-chelation. Only RG showed a weak Cu²⁺-chelation activity, which was more evident at 295 nm. Based on previous data with aged garlic extracts and some individual garlic compounds such as S-ethylcysteine, N-acetylcysteine, diallyl sulfide, and diallyl disulfide , we expected that our garlic extracts had Cu²⁺-chelating activity. The discrepancy with our data may simply reflect differences in composition in each garlic extract. This is additionally supported by the fact that the diethyl ether extract from aged garlic extract has no Cu²⁺-chelating activity²⁷.

Aged garlic extract increases the level of SOD, GSH and GPx in vascular endothelial cell and inhibits oxidative-stress mediated ischemic-reperfusion damage in rat brain. We have also reported that chronic oral administration of raw garlic homogenate caused a significant increase in basal SOD and catalase activities of rat heart, which was associated with a concomitant decrease in basal lipid peroxidation. Simultaneous increase in SOD and catalase activities, as observed with chronic administration of garlic homogenate has special importance of being more beneficial than increase in SOD activity alone, because without a concomitant increase in catalase activity, increased SOD activity may lead to intracellular accumulation of H₂O₂with detrimental effects. Protection against ischemia reperfusion induced oxidative stress in garlic treated rat hearts was evidenced by preservation of endogenous antioxidants and prevention in rise of TBARS. Among the three garlic treated groups, only 250 mg/kg group showed the best protection in terms of biochemical and histopathological evidences. Garlic in 125 mg/kg group did not show better histopathological improvement compared to garlic 500 mg/kg group. This can be explained by our previous study where only 250 and 500 mg/kg doses of chronic garlic administration augmented both SOD and catalase activities, while 125 mg/kg garlic administration augments only SOD activity²⁸.

Aged garlic extract, but not the fresh garlic extract, exhibited radical scavenging activity. The two major compounds in aged garlic, S-allylcysteine and S-allylmercapto-L-cysteine, had the highest radical scavenging activity²⁹.

Increase in lipid peroxidation following acute adriamycin administration, was significantly prevented by both the doses of garlic and this effect was comparable with that of probucol treatment. The improvement in myocardial TBARS was much less with the higher dose than with the lower dose. This can be explained by the fact that basal TBARS value was higher after chronic garlic treatment in 500 mg/kg dose than 250 mg/kg dose. The paradoxical rise in the level of reduced glutathione in adriamycin-induced cardiotoxicity was blunted in garlic as well as probucol treated hearts. This supports our hypothesis (as mentioned before) of "trapping" of glutathione in its reduced form (GSH) in ADR treated rat heart, which was postulated to occur due to reduction in GPx activity. Rise in GSH level was absent in garlic and ADR-treated rat hearts due to prevention of reduction in myocardial GPx activity. Significant preservation of myocardial catalase and GPx activities was seen with 250 mg/kg dose of garlic, whereas significant preservation of myocardial SOD and GPx activities was seen in 500 mg/kg garlic treated group. Although myocardial protection was observed in garlic (250 and 500 mg/kg) and probucol treated groups, 500 mg/kg dose of garlic seems to be better as evident from the histopathological studies supporting the earlier statement of the significance of simultaneous increase in SOD and GPx activity in mitigating oxidative stress. Expression of various cytokines, especially that of TNF-α is enhanced in various pathophysiological states, associated with increased oxidative stress, which in turn promotes the induction of various other cytotoxic substances on endothelial cells and myocytes. This has profound pathological significance, in terms of development of cardiomyopathy, myocyte apoptosis, transmural myocarditis and biventricular fibrosis as well as overall functional deterioration of heart. Adriamycin, in our study, caused marked TNF-α expression in the subendocardial region, myocardial cells and intramyocardial vessel wall. It is possible that increased oxidative stress following adriamycin administration caused expression of TNF-α. Oxidative stress is known to activate P38-mitogen activated protein (MAP) kinase and nuclear factor kappa B and thus play a role in the sequence of signaling events involved in myocardial TNF-α production. To the best of our knowledge, expression of TNF-α in heart of ADR-treated rat is reported for the first time in the present study. Probucol, as well as 250 mg/kg and 500 mg/kg of garlic treatment reduced the myocardial expression of TNF-α, following adriamycin administration which was associated with reduced myocyte injury, an effect which might be attributed to reduction in oxidative stress³⁰.

Pesticidal activity:

Effective pesticides have been developed from garlic extracts. Field trials carried out on mosquito breeding sites at Bombay (now Mumbai, India) have shown that garlic oil is very effective on several species of mosquitoes. The toxic effect of crude methanolic extract and garlic oil against 3rd stage of larvae of Culex peus, C. tarsalis, Aedes aegypti, A. trisoriatus, A.sirensis and 3rd and 4th stage larvae of highly insecticide resistant strains of A. nigromaculis. They reported that partially purified oil fraction was more toxic than the crude extract. Later, the larvicidal principles of garlic oil have been isolated and identified as diallyl disulfide and diallyl trisulfide. Allicin inhibited malaria infection by inhibiting cysteine protease, which processed circumsporozoite protein (CSP) of Plasmodium sporozoites for invasion of host cells. These compounds were fatal to Culex pipiens quinquefasciatus. Raw garlic juice at a dose 5 ml/kg body weight caused death of rats due to stomach injury. Root-dip treatment for tomato seedlings in 25 ppm allicin for 5 min is effective against nematode Meloidogyne incognita. Concentration of 200 and 100 ppm allicin as bareroot dips for 30 min killed 83% and 87% of M. incognita of tomato seedlings, respectively. The insecticidal activity of garlic juice in two dipterian pests Delia radicum (LC50- 0.4%) and Musca domestica (LC50- 2.2%). Garlic juice is effective against all the life stages of both insects.Ajoene, the major bioactive compound derived from garlic, showed a potent leishmanicidal activity in in vitro against Leishmania mexicana and L. donovani .The 50% inhibitory concentration (IC50) for lysis was about 2 M. They reported that leishmanicidal activity of ajoene is due to the morphological alteration of the mitochondrial membrane and nuclear envelope, as well as the formation of large autophagic vacuoles. Garlic extract has mild protective effect against Leishmania donovani. The homopteran sucking insect Lipaphis erysimi (mustard aphid) causes severe damage to various crops. This pest not only affects plants but it also transmits single-stranded RNA luteoviruses while feeding, which cause disease and damage in the crop. The mannose-binding garlic leaf lectin has been found to be a potent control agent of L. erysimi on one hand and on the other symbionin mediated luteovirus transmission.The water extract of garlic bulb is a potential source of molluscicide against Lymnaea acuminata and Indoplanorbis exustus. These snails are the intermediate host of liver fluke Fasciola hepatica and F. gigantica, which causes 94% fascioliasis in the buffalo’s population of northern India.Allicin is the main molluscicidal component of garlic. The toxicity of allicin (LC50 -3.64 mg/l) at 96 h exposure is 4.1, 4.2 and 2.5 times higher with respect to synthetic molluscicides (phorate, carbaryl and formothion, respectively). There was a progressive increase in the toxicity (8.67 fold) of garlic bulb extract against Lymnaea acuminata in the pre-harvest (2 to 5 months) period while in the post-harvest period (5 to 11 months) it was 5.5 fold .Significant increase in toxicity of pre-harvest garlic is due to increase in level of alliin. Increase in molluscicidal activity of garlic in post harvest period is due to some changes in the chemical composition of garlic bulb. The treatment of snail with sublethal concentrations of allicin caused a significant inhibition of acetylcholinesterase (AChE), lactic dehydrogenase (LDH) and alkaline phosphatase (ALP) activity in the nervous tissue of Lymnaea acuminata. Kinetic studies demonstrated that the inhibition of AChE by allicin was uncompetitive whereas inhibition of LDH and ALP was competitive.Inhibition of this enzyme by allicin in the nervous tissue of snail L. acuminata may be the cause of the molluscicidal action of garlic².

Hair re-growth inducing activity:

Different researchers have shown that alopecia areata is marked by autoimmune assault on the hair follicle resulting in hair loss. The modulatory effects of garlic on immune responses may justify its efficacy in alopecia areata Onion and garlic belong to a widely grown vegetable family named Asparagus . Both of them contain diallyl disulfide, which may provide their therapeutic effects. Though different modalities of treatment, local and systemic, have been used to induce hair re-growth, all of them have their own complications and efficacies. The high spontaneous remission rate of alopecia areata, sometimes makes it difficult to clearly assess the true efficacy of a given therapy. Topical garlic gel treatment may be effective and well tolerated in alopecia areata patients and provides prolonged therapeutic benefits³¹.

Antidepressant-like activity:

Garlic extract did not show significant change in the locomotor activity of mice, as compared to the control group; so this extract did not produce any motor effects. It confirms the assumption that the antidepressant-like effect of the extracts is specific. According to our results, the antidepressant-like effect of garlic extract was significantly reversed by the treatment of animals with prazosin (α₁ -adrenoceptor antagonist), sulpiride (a selective dopamine D₂ -receptor antagonist), p-CPA (serotonin synthesis inhibitor) and baclofen (GABA_B agonist) when tested in TST. This suggests that garlic extract might produce antidepressant-like effect through interaction with α₁ -adrenoceptors, dopamine D₂ receptors, serotonergic and GABAergic receptors, thereby increasing the levels of norepinephrine, dopamine, serotonin and decreasing GABA levels in the brain of mice.Garlic extract (100 mg/kg p.o.) administered to mice, for 14 successive days, significantly decreased brain MAO-A and MAO-B activities as compared to the control group. MAO inhibiting activity by the extract was comparable to imipramine. Thus, antidepressant-like activity of the extract might also be due to inhibition of MAO, resulting in increase in the brain levels of monoamines.Garlic extract showed significant antidepressant-like activity probably by inhibiting MAO-A and MAO-B levels, and through interaction with adrenergic, dopaminergic, serotonergic and GABAergic systems. The antidepressant-like action of the extract was comparable to imipramine and fluoxetine. Hence, garlic extract may have potential therapeutic value for the management of depressive disorders. Garlic extract (25, 50 and 100 mg/kg) significantly decreased immobility time in a dose-dependent manner in both TST and FST, indicating significant antidepressant-like activity. The efficacy of the extract was found to be comparable to fluoxetine (20 mg/kg p.o.) and imipramine (15 mg/kg p.o.) in both TST and FST. The extract did not show any significant effect on the locomotor activity of the mice. Prazosin, sulpiride, baclofen and p-CPA significantly attenuated the extract-induced antidepressant-like effect in TST. Garlic extract (100 mg/kg) administered orally for 14 successive days significantly decreased brain MAO-A and MAO-B levels, as compared to the control group.

Garlic extract showed significant antidepressant-like activity probably by inhibiting MAO-A and MAO-B levels and through interaction with adrenergic, dopaminergic, serotonergic and GABAergic systems³².

Neuroprotective activity:

Approximately 10% of persons older than 65 years have Alzheimer’s disease. The hallmarks of the disease are deposits of beta amyloid protein (Abeta) in the brain and neuron death that also occurs after an ischaemic event and stroke that rob the brain of oxygen and nutrients and can lead to dementia. AGE has potential to protect the brain against neurodegenerative conditions^46-51,by preventing brain injury following ischaemia, protecting neuronal cells against apoptosis, by inhibiting caspase and preventing A-beta induced oxidative death.S-allyl cysteine also prevents neuronal death following ischaemia and increases cell survival in the hippocampus, the memory region of the brain, by 30%,compared to controls³⁹ .

The effects of diallyl disulfide (DADS), a garlic derived compound, on the viability of neuronal cells and cell signals including phosphatidylinositol 3- kinase (P13 K), glycogen synthase kinase-3 (GSK-3) cytochrome c, caspase -3 and poly (ADP- ribose) polymerase (PARP) in PC12 cells neuronally differentiated by nerve growth factor. To evaluate the protective effects of DADS on oxidative stress–induced nPC12 cells, the viability of the cells (pretreated with DADS for two hours vs not pretreated) was evaluated 24 hours after exposure to100 µM H₂O₂ for 30 min. Compared to the cells treated with 100µM H₂O₂ only, pretreatment of the cells with 20µM DADS before exposure to 100µM H₂O₂ increased the viability and induced activation of P13K, inactivation of GSK-3 and inhibition of cytochrome C release, caspase-3-activation and PARP cleavage. These results indicate the neuroprotective effect of DADS by its anti-apoptotic properties.

Anti-allergy Activity:

Allergies, produced by the release of histamine from mast cells, in response to a stimulus, can interrupt our daily lives in most unpleasant ways. Treatment of histamine-releasing cells with AGE, prevented histamine release by 50% to 90 %, depending on AGE dose²⁵. Preclinical studies showed that AGE reduced allergic reactions by 24 - 45% following exposure to skin irritants or by an allergant injected into the blood circulation^39-40.

Immune booster:

Arachidonic acid acts as a precursor of eicosanoids, which are involved in many regulatory processes. Modification of arachidonic acid metabolism has been proposed to be a consequence of garlic’s action. Inhibition of eicosanoid synthesis affects eicosanoid-dependent regulatory processes, including those on immune response and anti-tumor immunity. A study done to investigate arachidonic acid metabolism and immune response gave rats garlic oil, diallyl disulfide (200 mg/kg of body weight) or corn oil three times a week for 7 days. The study demonstrated that garlic oil acts as an immunomodulator by promoting T-lymphocyte function. Garlic oil also was found to inhibit hepatic 6-desaturase activity and decrease the arachidonic acid concentrations in hepatic membrane phospholipids, both of which showed immunomodulatory potential. A study compared aged garlic extract, containing 1.6-2.4 mg/g (calculated as dry weight) of S-allylcysteine and solid materials, to 100 mg of Krestin (an anti-cancer medication) on mouse spleens. Aged garlic extract stimulated the proliferation of mouse spleen cells and the release of cytokines, such as IL-2, TNF-alpha, and IFN-gamma, increased NK activities and it enhanced phagocytosis of peritoneal macrophages. Aged garlic extract also stimulated reactivity of lymphocytes in response to cytokines and mitogens. Aged garlic extract was found to be as effective as Krestin in significantly inhibiting the growth of Sarcoma-180 and LL/2 lung carcinoma cells transplanted into mice.

The immune system consists of many types of cells and protective substances that fight infections and help battle life threatening diseases, such as cancer. A strong immune system defends against bacteria, viruses and fungal diseases. When immunity is damaged, such as in the case of AIDS, or compromised by poor diet, stress, environmental pollution, disease and ageing the body is at a loss to fight off infectious organisms. AGE has been shown to stimulate immunity and help combat infection^41.

Artery and heart protector:

A new breakthrough from the University of California (LA) shows that AGE cuts heart attack risk factors.¹¹ In a year long, double blind, placebo controlled, clinical trial nineteen cardiac patients, on statin therapy, who received 1 200 mg AGE/day, reduced coronary plaque build-up by more than 67%, as measured by electron beam tomography, and improved HDL, compared to placebo.55AGE also lowered blood homocysteine, while patients on placebo showed an increase.

The UCLA study, adds new critical information to the body of data showing that AGE reduces multiple risk factors associated with heart disease. These include an anticlotting effect, stimulation of blood circulation in capillaries⁴³, anti-inflammatory effects, by inhibiting prostaglandin synthesis⁴⁴,protecting arteries from inflammation that accelerates clot formation⁴⁴and as seen above, reduction of LDL, triglycerides, blood pressure and inhibition of LDL oxidation.

Though the study was small, its striking results on coronary artery protection by AGE in people with heart disease is hopeful news for those at high risk for heart attacks. AGE can be added to other routine medications for heart disease, such as statins, without side effects, potentially enhancing treatment and helping to postpone the need for cardiac surgery. As for healthy people, adding AGE to the diet could serve as a health strategy, to help prevent atherosclerosis and maintain a healthy heart.

Antiulcer activity:

Garlic oil was evaluated for gastroprotective activity against ethanol induced ulcers. Reactive oxygen species are involved in the pathogenesis of these ulcers. The possible involvement of garlic oil in restraining the oxidation process produced in gastric tissue was also investigated. The ulcer index, lipid peroxidation and antioxidant enzyme activity (GPx, catalase, SOD) were determined. Pretreatment with garlic oil in doses of 0.25 and 0.5 mg/kg, 30 min before administration of ethanol (1 mL of 100%) caused a decrease in ulcer index and lipid peroxidation and ameliorated the decrease in antioxidant enzyme levels caused by ethanol. The result suggests that garlic oil possesses antioxidant properties and provides protection against ethanol induced gastric injury⁴⁵.

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Received on 02.02.2009 Modified on 09.08.2009

Asian J. Research Chem. 2(3): July-Sept., 2009, page 225-234