Pharmacological effect of Allium sativum on coagulation, blood pressure, diabetic nephropathy, neurological disorders, spermatogenesis, antibacterial effects

1.   Introduction

From long ago and in many different old civilizations, different plants have been used as drugs and in order to treat and prevent from various diseases ^[1,2]. Garlic (Allium sativum L) is an edible and medicinal plant from Lilliaceae family which was being used in ancient Iranian medicine in treating different diseases ^[3,4]. In his law book, Avicenna has mentioned garlic as a useful plant in the treatment of joint diseases, dent pains, chronic cough, parasitic infections, snake bites, women's and diseases, infections and headaches, especially one way headaches ^[5]. Due to the widespread belief of the therapeutic properties of garlic among the people, it has been especially paid attention to in the modern medicine as a medicinal plant, too ^[3,4]. Also nowadays, widespread researches are done about the compounds existing in the garlic and its therapeutic properties. According to the investigations done, the main and effective material in juice extracted from the garlic or row garlic is called homogenized allicin ^[6].

2.   Diabetic nephropathy

During the recent decades, a huge rise has been occurred for using the medicinal plants and traditional medicine in order to treat diabetes disease and many other diseases. For example, some plants such as onions, ginger and aloe vera can be mentioned. Garlic has medicinal and therapeutic properties such as antibacterial, anticancer, anti-asthma and anti-diabetes properties ^[7]. Many widespread researches have been done on the anti-diabetic properties of the garlic and it has been cleared that its Sulphuric compounds like allicin act as the hypoglycemic compounds. Also, it has been determined that the 15-day treatment with the garlic oil cause a significant increase in Albumin serum ^[8]. On the other hand, nephropathy and toxicity created with potassium dichromate cause the oxidative stress in kidney and consuming garlic powder improves the consequences caused by it so that the mice feeding with garlic powder prevents from the significant changes of renal injuries for 2 percent and improves 55 percent of textural injuries caused by potassium dichromate in mice's kidneys ^[9]. During many studies which have been done in the field of the anti-diabetic properties of garlic and its compounds, most of them have confirmed the garlic's anti-diabetic properties ^[10].

In 2011, Ryan indicated that the disease of one third of the patients with diabetes disease who regularly consumes garlic along with their medicinal treatment has been improved effectively. Dimirdash ^[11] found out that the garlic's juice reduces the blood sugar of the groups receiving garlic. Also the garlic's oil and the compounds existing in garlic such as diallyl trisulfide improve the blood sugar levels of diabetic rats ^[12]. The studies done on the garlic's oil have indicated that the garlic improves the textural changes caused by nephropathy during diabetes disease ^[6]. Advancing renal damages and high blood pressure are depended upon oxidative and nitro-oxidative stress and consuming the garlic oil and S Allil Cysteine (SAC) reduces the blood pressure and renal damages and it does this work through improving antioxidant system and delaying the renal damages caused by diabetes disease ^[13].

Also increasing blood sugar during diabetes induces growth factors and cytokines which results in increase of glomeruli growth and expanding the extracellular matrix and creation of sclerosis and finally fibrosis of the renal texture ^[14]. The studies have indicated that garlic consumption releases the growth factors and cytokines; therefore, other possible mechanisms of the garlic can be named in reducing the tubular damages and preventing from the release of growth factors and cytokines and also reduction of inflammation factors which result in improvement of hypertrophy of glomerulus and tubules ^[15].

The oxidative stress increases significantly during diabetes. Also the induction of oxidative stress in kidney using gentamicin increases producing free radicals in kidney which results in destruction of kidney texture (necrosis of proximal tubules). On the other hand, the researchers have indicated that the garlic and its compounds have strong antioxidant properties due to the sulfur compounds such as (SAC ^[16] and diallyl trisulfide ^[12]) and the garlic is likely to reduce the damages caused by diabetic nephropathy through increasing the antioxidant amount in the kidney ^[17].

Also the studies have indicated that the proportion of kidney weight to the body weight increases in diabetic patients ^[18]; hence, the results of this study have also indicated that the proportion of kidney weight to the body weight increases during diabetes and consuming garlic oil reduces this proportion in the groups receiving garlic. According to the investigations done by the researchers, it has been cleared that the blood sugar increase in diabetes increases the intercellular protein synthesis and decreases the catabolism of proteins; and this decreases also increases the cells' length and the volume of cellular proteins which result in the hypertrophy of glomerulus and tubules. On the other hand, it has been indicated that in diabetes disease, the activity and production of intracellular proteases like cathepsin ^[19] significantly decreases due to the increase in production of factors such as TNF- α and Angiotensin ll, and this cause hypertrophy of glomerulus and kidney texture. Since the garlic decreases the production of cytokines ^[20], so it also prevents from hypertrophy in this way.

Shiju TM, et al. ^[21] showed that aged garlic extract was able to ameliorate kidney damage an animal model. They revealed that anti-glycation and hypolipidemic activities of aged garlic extract caused renoprotective impacts.

Aged garlic extract has been indicated to have antioxidant ^[22], anti-thrombotic ^[23], anti-cancer ^[24], hypoglycemic ^[25], hypolipidemic and hypocholesterolemic activities ^[26]. The renoprotective effect of aged garlic extract on nephrectomised ^[13,27,28] and nephrotoxic rat models ^[29,30,31] has been reported. Ilker Seckiner, et al. ^[32] indicated that 4% pulverized garlic supplemented diet has preventive role aganist nephrotoxicity induced by gentamicin in rats.

3.   Antibacterial effects

In some studies, it has been emphasized on the existence of a relationship between garlic consuming and decrease in helicobacter pylori infection ^[33,34,35]. However in some other studies such a relationship has not been observed ^[36,37,38].

The recent studies have indicated that due to having allicin, the garlic has antibacterial characteristic on a wide range of positive gram and negative gram bacteria especially on helicobacter pylori so that analyzing or preventing from allicin formation removes the antibacterial activity of the garlic ^[39,40].

Naturally there is no allicin in the garlic, but also it is produced after hydrolyze and oxidation of a material named allin ^[41]. In case of cutting or grinding the garlic cloves, the destruction of garlic cells and allinase enzyme changes the allin material into the unstable form of allicin Thiosulfinate and after that allicin ^[42]. According to the study, the garlic's effect mechanism is done through preventing from the activity of nuclear factor Kappa (KB) ^[43].

This factor increases the expression of genes related to inflammation cytokines and it is considered as one of the key molecules in inflammation and cancer. Activation of this nuclear factor is done through signaling the receptors called (Toll-like receptors) TLR 4.TLR 4s are the key receptors in feeling the different microbial productions and stimulating the immune responses ^[43]. These receptors have several compounds containing cysteine in their cytoplasm and extracellular parts.

The studies have indicated that the allicin existing in garlic contains some compounds called Thiosulfinate which can react to cysteine ^[43]. As a result, allicin may react to this cysteine existing in the structure of these receptors and prevent from the activity of signaling paths depending upon TLR 4 on the surface of the cellular receptors. Allicin prevents from the activation of nuclear factor of KB through blocking TLR 4 signaling ^[44].

This prevention is considered as one of the anti-inflammation mechanisms of the garlic. In addition to the mentioned mechanisms, the previous studies have also indicated that the helicobacter pylori produce some antigenic materials such as heat shock proteins, urease and lipopolysaccharide which all of them can be absorbed by the epithelial cells of the gastric and pass the sub-mucosal layer and ultimately make the inflammation factors od CRP and IL-8 and TNF- α synthase ^[46].

While the Thiosulfinate existing in garlic have the ability to rapidly react with the SH group existing in these compounds and cause the prevention of activation of these compounds and ultimately decrease in colonization of this microbe ^[47]. Helicobacter pylori increases PH in the gastric and this is followed by the increase of nitrate quickening microbes in the gastric and as a consequence nitrite level which is an important factor of cancer development increases ^[48]. Allicin may decrease the helicobacter infection and also the cancer development through blocking the nitrous construction and the cleaning role of nitrates and free radicals ^[48].

In the previous studies it has been indicated that firstly, in the grinding process of the row garlic, the antibiotic properties of allicin existing in it decreases ^[49]. Secondly, storing garlic powder for a long time also decreases the antibiotic properties of allicin, because allicin is analyzed to the other sulfuric compounds in a long time period and however these compounds have therapeutic properties in their turn, but they cannot induce the potential antibiotic properties of allicin on the bacteria ^[49].

Developing resistance in different species of helicobacter pylori against the antibiotics is a thousand times easier than developing it against allicin ^[50]. In addition, the previous studies have indicated that not only the helicobacter pylori do not become resisted against allicin, but also, consuming garlic along with the antibiotics additionally influences the eradication of this bacterium ^{[51,52,53,54]}.

4.   Spermatogenesis

Garlic's biological responses include reduction of cardiovascular risk factors, cancer, stimulating immune activity, increased detoxification of foreign compounds, anti-microbial and anti-viral effects, antioxidant activity, protecting from germinal cells in adult male rats that reflect their antioxidant role, protecting from sperm and the cause of ultimate maturation of sperm and its evolution. It has been reported that adding the garlic extract to the drinking water of male rats for a three months period has increased the epididymis's and seminal vesicle weight compared to the normal rats; and also the number of sperms increases significantly ^{[55,56,57,58]}.

Garlic has different compounds such as prostaglandins, pectin, adenosine, vitamins E, C, B6, B2, B1, A, biotin, fatty acids and essential amino acids ^[49].

Several therapeutic effects and numerous properties have been mentioned for this plant so that it has been considered as the disinfectant of digestive tract, stimulant plant, diuretic and appetizer ^[59,60].

Mammalians sperm cells have a high amount of unsaturated fatty acids, plasmalogen and Sphingomyelin which are considered as the important substrates in oxidation process ^[61]. The antioxidant mechanisms are normally present in the reproductive textures and they prevent from the oxidative damages in Gennady and adult spermatozoa cells ^[62,63]. On the other hand, the intrinsic antioxidant activity of garlic, its extracts and some of its compounds has been widely confirmed in laboratory environments and organisms. It has been cleared that garlic consumption increases the serum level of the total antioxidant potential. The garlic extract increases the superoxide dismutase (SOD), glutathione peroxidase and catalase in the cells ^[64].

The studies indicate that increase of free radicals negatively influences the reproduction, activity and fertility of sperms. If these radicals' level is not regularly balanced, the normal performance of cells is hindered. According to the studies done, the complex process of spermatogenesis and passing the germinal cells to reach the matureness of the sexual cells depend on being secured from the pathologic and cytotoxic wastages which threaten this phenomena ^[65].

Antioxidant activity of garlic is due to the sulfur compounds existing in it and they are seen in the garlic extract abundantly. This antioxidant activity eliminates the free radicals and also prevents from the active metabolite of cyclophosphamide active drug (Acroleine) and eliminates them ^[66,17].

The studies indicate that the garlic extract protects the germinal cells in matured adult rats and this property can be the reflection of its antioxidant role ^[67].

Glutathione peroxidase enzyme plays an essential role in protecting sperms in testicle and the epididymis texture as an antioxidant; and decrease in this enzyme in the body causes infertility. This enzyme locates in plasma membrane of the sperm, the sperm cell, epididymis liquid and epididymis area and in this way it protects the sperms from the free radicals and this leads to ultimate matureness and development of them ^[68].

The studies indicate that the antioxidant enzymes, glutathione peroxidase and superoxide dismutase protects the cells through influencing peroxide forms and oxidation reduction. Garlic extract increases the cellular glutathione peroxidase enzyme in all the cells of liver, kidney, breast, testis, etc. ^[66,67]. Therefore, the garlic extract and especially diallyl disulfide and other sulfur compounds prevent from the destructive influences and DNA break in sperm and sperm-germinal cells through increasing glutathione peroxidase.

In the studies done, the garlic juice protects the germinal cells of male rats and this can be the reflection of its antioxidant role ^[69].

In 2008, it has been reported that the ethanol extract of rhizome which is called with the scientific name of Curculigo orehioids increases the spermatogenesis in testis of albino rats. This plant has phenol and phenolic glycosides which have antioxidant properties. According to the effects mentioned about phenolic glycosides existing in rhizome, and due to the fact that this compound also exists in the garlic, it can be said that this compound is one of the active and effective components of the garlic in increasing the spermatogenesis ^[67,70].

Garlic has melatonin which prevents from the degeneration with germinal cells as a strong antioxidant. Melatonin simulates the internal antioxidant system and increases the activity of glutathione S-transferase, superoxide dismutase and the other thiols in blood, liver, testis and kidney ^[71,72,73].

The study ^[74] indicated that the garlic extract influences the increase of releasing the matured sexual cells in addition to influencing the structure of sperm generating ducts and it also improves the spermatogenesis process in experimental groups receiving cyclophosphamide. Cyclophosphamide prevents from reproduction of the germinal cells through influencing DNA molecule and as a consequence, it decreases the number of sperm cells, spermatid, and the primary and secondary spermatocyte. Due to the sulfuric compounds in the garlic, its antioxidant activity eliminates the free radicals and also prevents from the active metabolite of cyclophosphamide (Acroleine) and eliminates it. Probably, inclusion of this plant which is full of useful and effective compounds in the diet of those whose fertility (reproductive activity) has been impaired sue to consumption of chemical drugs can be influential in treating this impairment (inability in reproduction).

5.   Neurological disorders

In recent decades' researches, in addition to the stabilization of the garlic's role in treating the diseases especially cardiovascular diseases, its role in treating the central nervous system side effects has been confirmed ^[75]. According to the study done, garlic has anti-stress, anti-aging properties and it improves memory and learning ^[76,77,78]; moreover, old garlic extract have protecting effects on the brain and prevents from oblivion, neuronal apoptosis, Alzheimer and the other neurodegenerative diseases ^[75,79,80].

Dhingra indicated that the alcohol extract of garlic can have anti-depression properties through inhibition of monoamine oxidases and increase in norepinephrine, dopamine and serotonin level, and decrease in GABA levels in the rat's brain; also the garlic may have mutual function with different brain receptors including α1 adeno-receptors and D2 dopamine receptors, GABAergic and serotonergic receptors ^[81].

The previous human and animal studies have indicated the anti-pain effects of the garlic so that it decreases dental pain, colic gastrointestinal pains, the pains caused by inflammation of the middle ear, chest pains and the intermittent claudication pain which is due to peripheral vascular obstruction ^{[82,83,84,85]}. Although, no conclusive reason has been mentioned for this anti-pain property of the garlic in these studies, the previous animal studies have shown that the old garlic extract can prevent from the memory and learning disorders which are caused by aging ^[76,85]. Also, in these studies it has been determined that the garlic is able to prevent from the frontal brain shrinkage of the old rats' brains, atrophy and reduction of brain size ^[76].

In his review study, Borek has emphasized on the fact that the garlic can prevent from the brain's side effects caused by aging including Dementia, oblivion and Alzheimer; however, he considers the anti-oblivion property of the garlic the reason of prevention of these factors due to the shared risk factors among the cardiovascular diseases and oblivion and Alzheimer such as blood pressure, increase in blood cholesterol and homocysteine levels and inflammation and the fact that the garlic prevents from the cardiovascular diseases; also, regarded to the role of free radicals in these diseases and its antioxidant properties, they can be the reason.

At the end of the study, the author considers the treatment with old garlic extract useful in preventing from degeneration of brain's frontal lobe, memory loss and learning and increase in lifetime ^[75]. In the other studies, the anti-stress effects of garlic have been confirmed ^[77]. A study indicated that in the presence of old garlic extract, the cultured hippocampus neurons grow more and the number of their branches increases; this characteristic can be the indicator of the reason of garlic's effect on increasing learning and cognitive functions ^[76]. S-Allil Cysteine (SAC) can prevent from the formation of Beta Amyloid caused by stress oxidative in hippocampus of rats and decrease the learning deficits; the authors consider these effects caused by antioxidant effects ^[86].

6.   Coagulation

Acting against the microorganisms, and anti-cancer, anti-intoxication, anti-inflammation activities are from the numerous and useful properties of garlic which reduces the blood pressure and sugar, simulates immune system and it is anti-allergy and anti-goiter ^{[87,88,89,90,91,92,93,94]} and also it has anti-coagulation properties and in this regard, it improves the activity of warfarin and nonsteroidal anti-inflammation drugs' influence ^{[95,96,97,98,99,100,101,102,103,104,105]}.

In his study, lee Moffitt considers the existence of adenosine de-amines and cAMP phosphodiesterase in garlic as one of the important reasons of anti-coagulation and vascular dilator properties of this plant ^[100]. Also, the compound of Ajoene existing in garlic is a strong anti-platelet agent which inhibits the platelet agammaession reversibly and in the form of Invitro and anyway it influences the BT process. Ahmad-Ni-Lavrik et al. have also emphasized on the adverse effect of garlic on the platelet activity; however, many researchers including Jabbari and Hagdan emphasize that in order to determine the clear effect of garlic on blood pressure-inhibition of platelet and fat agammaession, etc. it is required to consume it for three months ^[98,99]. One of the most important issues which has been referred in different references ^{[95,97,100,101]} is the simultaneous consumption of garlic with anti-coagulation drugs like warfarin or nonsteroidal anti-inflammation drugs like aspirin, the garlic can intensify their effect and lead to bleeding.

Anesthesiologists and some researchers emphasize on not consuming garlic before surgeries because of the increased bleeding risk ^[95,97,100].

Fakhar and Hashemi ^[104] revealed that garlic as a supplementary treatment can decrease platelet agammaegation.

7.   Blood pressure

There has been reported that garlic has anti-hypertensive effect through mechanism of intracellular nitric oxide and hydrogen sulfide production besides reducing the production of angiotensin-Ⅱ ^{[105,106,107,108,109,110,111,112]}.

8.   Conclusions

Regarded to the antioxidant properties of the garlic which has been previously confirmed, it is likely to reduce these damages significantly through increasing antioxidant capacity in the kidney. Due to the mentioned results, we indicated that the garlic is able to prevent from the diabetic side effects of kidney. The results findings indicate that advising to consume garlic along with antibiotic can help reduce and eradicate helicobacter pylori and the other bacteria. Finally, it must be mentioned that however the garlic has been posed as a factor for reducing infection, but there are still many ambiguities in this regard.

There are numerous reports about the anti-coagulation properties of the garlic. Also there have been some warnings about its simultaneous consumption with warfarin and nonsteroidal anti-inflammation drugs. In this research, it has been tried to investigate the influence of garlic on the coagulation tests in order to guide the patients especially the ones with coagulation problems better about how to consume garlic in case of the proved adverse effects on the coagulation process. Anesthesiologists and some researchers emphasize on not consuming garlic before surgeries because of the increased bleeding risk. Also garlic has the anti-blood pressure properties and its compounds have been studied for treating infertility.

According to the study done, garlic has anti-stress, anti-aging properties and it improves memory and learning; moreover, old garlic extract have protecting effects on the brain and prevents from oblivion, neuronal apoptosis, Alzheimer and the other neurodegenerative diseases.

Conflict of interest

The authors declare no conflict of interest.