CHEMICAL CONSTITUENTS AND PHARMACOLOGICAL EFFECTS OF LEPIDIUM SATIVUM -A REVIEW

Lepidium sativum contained many bioactive constituents included cardiac glycoside, alkaloids, phenolic, flavonoids, cardiotonic glycosides, coumarins, glucosinolates, carbohydrates, proteins and amino-acids, mucilage, resins, saponins, sterols, tannins, volatile oils, triterpene, sinapic acid and uric acid. The pharmacological investigation revealed that Lepidium sativum possessed antimicrobial, antidiabetic, antioxidant, anticancer, reproductive, gastrointestinal, respiratory, anti-inflammatory, analgesic, antipyretic, cardiovascular, hypolipidemic, diuretic, central nervous, fracture healing and protective effects. The current review discussed the chemical constituents and pharmacological effects of Lepidium sativum . glucosinolates, carbohydrates, proteins and amino-acids, mucilage, resins, saponins, sterols, tannins, volatile oils, triterpene, sinapic acid and uric acid. The pharmacological investigation revealed that Lepidium sativum possessed antimicrobial, antidiabetic, antioxidant, anticancer, reproductive, gastrointestinal, respiratory, anti-inflammatory, analgesic, antipyretic, cardiovascular, hypolipidemic, diuretic, central nervous, fracture healing and protective effects. The current review will highlight the chemical constituents and pharmacological effects of Lepidium sativum completely tissues shift while crude shifted isoprenaline curves. and antispasmodic activities mediated through activation of K channels, Lepidium sativum seeds powder was studied in acute renal failure in male albino rats. The results showed that feeding acute renal failure with seeds powder at 5% and 10% in curative and protective groups improved the body weight gain, feed intake and feed efficiency ratio. The diet fortified at 5% and 10% seeds powder helped to improve blood lipid levels as well as reducing hazards on kidney and liver function compared with positive control groups (injected with cisplatin, which were considered as a major risk factor for renal failure disease). Histopathologically, kidney of rats in curative and protective groups fed on basal diet containing seeds powder at 10% showed mild proximal tubules cell necrosis and minimal interstitial inflammation [90]. ATPase were significantly reduced after single- dose cisplatin injection and significantly elevated by treatment in curative and protective groups [89]. distal tubules, there a significant increase in tubular degeneration throughout the experiment. These results paired together show a significant toxic effect for rats fed 15% Lepidium sativum seed The effects of an aqueous Lepidium sativum seeds extract on the immune system and general health was studied in mice. An aqueous extract of ground Lepidium sativum seeds was orally gavaged to young adult male Swiss albino mice at a low dose (0.5 ml) and a high dose (1 ml) daily for 19-21 d. Results showed that Lepidium sativum seeds statistically significant increases in the mean white blood cell count and mean spleen weight in low dose group; however, for the high dose group, the increases tended to be more significant. The mean body weight for the high dose group showed clear increases compared to the control. The mean of white blood cell types, red blood cell, and platelet counts; mean hemoglobin concentration; mean total body gains; and weights of the organs (except for the spleen) were not significantly different for the low dose and high dose groups compared to the control [100].

β-sitosterol and some phytoestrogens were isolated from Lepidium sativum. The amount of β-sitosterol was estimated to be about 0.20% w/w for seed powder and 0.024% w/w for callus powder of Lepidium sativum. Daidzein and formononetin were also isolated from the samples of Lepidium sativum [36].
The seeds of Lepidium sativum also contained dimeric imidazole alkaloids, lepidine B, C, D, E and F and in semilepidinoside A and B [40].
Fractionation of the glucosinolate contents of the seeds of Lepidium sativum revealed the isolation of glucotropaeolin and 2-Phenyl ethyl glucosinolate, while, fractionation of the glucosinolate contents of the fresh herb revealed the presence of 2-ethyl butyl glucosinolate, methyl glucosinolate, butyl glucosinolate and glucotropaeolin [41]. 36.76% g/g dry weight mucilage was obtained from the callus culture of Lepidium sativum. The mucilage produced by callus culture was nearly three times more than the mucilage yield of the seeds. The (glucose, arabinose, mannose, and galactose) were 43.4, 195.3 and 86.2 mg/g dry weight in the mucilage originated from seed, callus leaf and callus hypocotyl, respectively [42].

Antimicrobial effects
The antimicrobial activities of methanolic seed extract of Lepidium sativum was studied against eleven bacterial strains ( . Antifungal study showed that the methanolic seed extract of Lepidium sativum was active against Aspergillus flavus, Aspergillus fumigates, Candida albicans and Saccharomyces cerevisiae with zones of inhibition of 7.01±0.11, 7.00±0.11, 6.99±0.14 and 7.00±0.17 mm, respectively. An antibacterial study showed that the methanolic seed extract of Lepidium sativum produced diameters of inhibition zones ranged from 6.03±0.27 to 0.04±0.01 mm against the tested bacteria [35]. The antimicrobial effects of extracts of Lepidium sativum were investigated against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Proteus vulgaris, Pseudomonas aeruginosa, Candida albicans and Aspergillus niger. The methanolic extract of Lepidium sativum possessed antimicrobial activity against Candida albicans (21 mm) and Proteus vulgaris (20 mm), Bacillus subtilis (13 mm), Staphylococcus aureus (13 mm), Escherchia coli (13 mm), Pseudomonas aeruginosa (13 mm) and inactive against Aspergillus niger. The chloroform extract showed very low activity against Staphylococcus aureus (12 mm) and Pseudomonas aeruginosa (12 mm), with no activity against Bacillus subtilis, Escherchia coli, Proteus vulgaris, Candida albicans and Aspergillus niger. The water extract showed antimicrobial activity against Bacillus subtilis (15 mm) and Escherchia coli (15 mm), with no effect against Staphylococcus aureus, Proteus vulgaris, Candida albicans and Aspergillus niger [44].  (18 mm). Hexane extract exhibited the greatest zone of inhibition against Candida albicans (16 mm) [46].
The antimicrobial activity of the petroleum ether, methanol and water extracts (2.5, 5 and 10%) of Lepidium sativum seed extracts was tested against Staphylococcus aureus, Escherichia coli, Klebsiella pneumonae, Proteus vulgaris, Pseudomonas aeruginosa and Candida albicans. The petroleum ether extracts of Lepidium sativum seeds in different concentrations showed antimicrobial activity against all the tested microorganisms with strong anti-Candida activity at the concentration of 2.5 and 10%. Staphylococcus aureus and Candida albicans were resistant to 2.5 and 5% water extracts, whereas Candida albicans was also resistant to 5% methanolic extract [20].
Lepidium sativum seed oil extracted by soxhlet and maceration was evaluate against Escherichia coli, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aureginosa, Staphylococcus aureus, Bacillus subtilis, Candida albicans and Aspergillus flavus. Lepidium sativum seed oil extracted by maceration was partially active against Escherichia coli at concentrations of 10 and 50 μg/ml, while the oil extracted by soxhlet showed no activity at these concentrations. At 50 μg/ml both samples were partially active against Klebsiella pneumonia. The soxhlet sample also exhibited partial activity against Bacillus subtilis at a concentration of 10 and 50μg/ml, while the macerated sample was inactive at these concentrations. Both samples were inactive against Staphylococcus aureus [34].
Methanol and ethyl acetate extract of the seeds of Lepidium sativum showed significant antibacterial activity against Rhodococcus equi [27].
The methanolic extract of Lepidium sativum seed was studied at different concentrations (10, 30, 60 and 90 mg/ml) against human pathogenic and opportunistic fungi (Aspergillus flavus, Aspergillus fumigatus, Candida albicans, Fusarium sp, Penicillium sp and Penicillium marneffi). The Aspergillus flavus was the most sensitive fungi, it inhibited at 30 mg/ml. Rhizopus sp. showed slow and weak growth on 30 mg/ml and 60 mg/ml slant and was completely inhibited at 90 mg/ml. At a concentration of 90 mg/ml, Aspergillus fumigatus, Candida albicans, Fusarium sp, Microsporum sp, Penicillium sp, Penicillium marneffi were completely inhibited [47].
The antifungal activity of ethanolic extract of Lepidium sativum seeds (2-8 mg) was evaluated against Fusarium equiseta, Aspergillus flavus and Alternaria alternate. The diameter of the inhibition zone ranged from 4 to 22 mm against the tested fungi [18].

Hypoglycemic effects
The hypoglycemic effect of the aqueous extract of Lepidium sativum seeds (20 mg/kg, orally for 16 d) was investigated in normal and streptozotocin-induced diabetic rats. Administration of the aqueous extract of Lepidium sativum seeds caused a significant reduction in glucose, creatinine, and alkaline phosphatase levels. Elevated cholesterol level was restored approximately to normal and a significant decrease in malondialdehyde levels was also observed compared to diabetic controls [47].
The hypoglycemic activity of the methanol extract (three concentrations for four weeks) of Lepidium sativum seeds was tested in alloxan-induced diabetic male rats. Treating of diabetic rats with Lepidium sativum methanol extract decreased blood sugar and restored all biochemical and histological changes to the normal [48].
The antidiabetic effect of Lepidium sativum seed alkaloid (50,150 and 250 mg/kg, ip for 21 d) was studied in alloxan-induced diabetic rats. Lepidium sativum seed total alkaloid at 250 mg/kg showed 1.94% body weight gain on 21 th The hypoglycaemic effect of an aqueous extract of Lepidium sativum seeds was investigated in normal and streptozotocin-induced diabetic rats. After a acute (single dose, 20 mg/kg) or chronic (20 mg/kg, 15 daily repeated administration) orally, the extract significantly decreased blood glucose levels in STZ diabetic rats (p<0.001); and normalised the blood glucose levels after 2 w daily oral administration of the extract (p<0.001). A significant reduction on blood glucose levels was noticed in normal rats after both acute (p<0.01) and chronic treatment (p<0.001) [50]. day relative to 6.14 and 8.94% of control and diabetic group. Lepidium sativum seed total alkaloid at the same dose significantly (p<0.001) suppressed blood glucose, cholesterol, triglyceride and urea level in diabetic rats [49].
The mechanism underlying the hypoglycaemic activity of the aqueous extract perfusion of Lepidium sativum was studied in normal and streptozotocin-induced diabetic rats. The aqueous extract at a dose of 10 mg/kg/h reduced blood glucose levels and increased glycosuria in normal (p<0.001) and diabetic rats (p<0.001). Oral administration of aqueous extract for 15 d normalized glycaemia (p<0.001), enhanced glycosuria (p<0.05) and decreased the amount of urinary TGF-beta1 (p<0.01) in diabetic rats [51].

Reproductive effects
The effect of tocopherol extracted from Lepidium sativum seeds on the fertility was studied in the adult male rabbit. The results showed a significant increase (p<0.05) in testicular sperm concentration, epididymus sperm concentration and in the sperm count per gm of the testis, sperm motility percent, grade activity, sperm viability percent, with a decrease in abnormal sperm morphology percent [52].
The possible protective effects of Lepidium sativum seed extract (200 and 400 mg/kg‚ orally) on fasting blood sugar and on the histopathological change of epididymis were studied in streptozotocin-induced diabetic rats. Administration of 200 and 400 mg/ml doses of Lepidium sativum seed extract increased epithelium height and decreased interstitial volume density and fibromuscular thickness significantly. Tubular and lumen diameter did not change significantly in different groups [53].
The effect of Lepidium sativum seed ethanol extract (200 and 400 mg/kg, orally) on fasting blood sugar and its protective effect on histopathological changes in the ventral prostate gland were studied in streptozotocine-induced diabetic rats. Administration of the 200 and 400 mg/kg doses of Lepidium sativum seed extract increased epithelium height and decreased interstitial volume density and fibromuscular thickness of the prostate significantly [54].
The effect of Lepidium sativum aqueous extract on the fertility criteria in males was studied in mice. The aqueous extract was given alone for 2 w, or after sulpiride for 6 w and then with the aqueous extract for 2 w. The results showed that the weight does not change over the first three weeks, but there was a significant increase in body weight at the fourth week. The group treated with both, sulpiride and Lepidium sativum aqueous extract showed the higher level of LH, while the group which was treated with Lepidium sativum aqueous extract only showed a higher level of FSH. Prolactin showed its lowest level in the group treated only with Lepidium sativum aqueous extract. Testosterone showed a higher level in the group treated only with Lepidium sativum aqueous extract. Histological sections for the testes in the group treated with Lepidium sativum aqueous extract only showed normal appearance of seminiferous tubule with presence of high number of sperms, sulpiride hyperprolactinemic mice testis showed partial degeneration and damage of dispersed spermatogonia cells with still presence of sperms inside the lumen with certain morphological abnormality in the shape of the sperms. Sections of treated mice testis showed a look like normal shape and structure of seminiferous tubules with the presence of normal morphology shape sperms in the lumen [55].
However, the effects of aqueous extract of Lepidium sativum seed on the development and magnitude of surge releases of GnRH, LH, FSH, testosterone secretion and spermatogenesis were studied in rat. Rats that received Lepidium sativum extract showed no changes in hormonal status and reproductive organs histology. The author concluded that there was no conclusive data for the aphrodisiac claims. There is a paucity of information on of Lepidium sativum seed effects on female reproductive function. Lepidium sativum seed has been shown in females to act as a galactagogue, abortifacient and contraceptive [56].
The effect of methanolic extract (200 and 400 mg/kg for 21 d) of seeds of Lepidium sativum was studied on proceptive and receptive behaviors of ovariectomized female Wistar rats. On 11 th and 21 st However, the effects of dietary supplementation of Lepidium sativum seed powder (0%, 5%, 7% and 10% w/w) on growth performance and gonadotropins secretion were studied in ovariectomized, estradiol implanted rabbits. Feed intake was significantly (p<0.05) increased in Lepidium sativum seed powder supplemented group, but its didn't increase body weight gain. Lepidium sativum seed powder supplementation significantly (p<0.001) increased mean plasma LH, dose-dependently from the low-to the mid-Lepidium sativum seed powder level and then decreased LH at the high-Lepidium sativum seed powder level. Lepidium sativum seed powder supplementation increased (p<0.001) plasma FSH secretion [58].
day, each female was tested in estrous phase for their sexual behavior in the copulatory test. Behavioral estrus was induced by subcutaneous administration of 25 μg estradiol benzoate 48 h prior to behavioral testing and 500 μg of progesterone 5 h before testing. As a measure of proceptivity, the number of hops, darts, ear wiggling and solicitations made by methanolic extract treated female rats were significantly increased when compared against control estrous females. Lordosis quotient, as a measure of receptivity, was unaffected by doses of methanolic extract [57].

Gastrointestinal effects
The aqueous-methanolic extract of Lepidium sativum seeds (30 and 100 mg/kg possessed atropine-sensitive prokinetic and laxative activities in mice, which were partially sensitive to atropine. In isolated gut preparations of mouse and guinea-pig, aqueousmethanolic extract (0.1-1 mg/ml) caused a concentration-dependent stimulatory effects both in jejunum and ileum, which was blocked by atropine. In rabbit jejunum, the stimulant effect of aqueousmethanolic extract remained unchanged in the presence of atropine, pyrilamine or SB203186, while in rabbit ileum, the stimulatory effect was partially blocked by atropine. The aqueousmethanolic extract was more efficacious in gut preparations of a rabbit than in guinea-pig or mouse. The phytochemical analysis of the plant extract revealed that it consisted of alkaloids [59].
The antidiarrheal activity of the methanolic extract of Lepidium sativum was investigated in three experimentally induced diarrhea models (castor oil-induced diarrhea; prostaglandin E2 induced enteropooling in rats and charcoal meal test in mice). In castor oil induced model, the methanolic extract (50, 100 and 200 mg/kg, po) showed the significant dose-dependent reduction of cumulative wet fecal mass. In PG-E2 induced enteropooling model, the methanolic extract (50, 100 and 200 mg/Kg, po) inhibited PG-E2 The seed extract of Lepidium sativum at 100 and 300 mg/kg inhibited castor oil-induced diarrhea in rats. In isolated rat ileum, the seed extract (0.01-5 mg/ml) reversed carbachol (1 µM) and K induced secretions. In charcoal meal test, the methanolic extract (50, 100 and 200 mg/kg, po) decreased the movement of charcoal, indicating its antimotility activity [60]. + (80 mM)-induced contractions with higher potency against carbachol. Preincubation of rat ileum with a lower concentration of seed extract (0.03 mg/ml) caused a rightward parallel shift in the concentration-response curves of carbachol without suppression of the maximum response, while at the next higher concentration (0.1 mg/ml), it produced a non-parallel rightward shift with suppression of the maximum response. The seed extract shifted the concentration-response curves of Ca ++ to the right with suppression of the maximum response. Accordingly, Lepidium sativum seed extract possessed antidiarrheal and spasmolytic activities mediated through dual blockade of muscarinic receptors and Ca ++ The antidiarrheal and antispasmodic activities of the crude extract of Lepidium sativum were further studied using in vivo and in vitro experiments. The crude extract inhibited castor oilinduced diarrhea in mice at 300 and 1000 mg/kg (three times higher dose than for rats). In isolated rat ileum and jejunum, crude extract completely inhibited carbachol, low K ⁺ (25 mmol) and high K ⁺ (80 mmol)-induced contractions while in Guinea-pig tissues, crude extract caused complete inhibition of only carbachol-induced contraction. In rabbit tissues, crude extract completely inhibited carbachol and low K ⁺ -induced contractions sensitive to K ⁺ channel antagonists. Pretreatment of Guinea-pig and rat tissues with crude extract caused a rightward shift in carbachol-induced contractions, while in rabbit and rat tissues, crude extract shifted isoprenaline curves. The results indicated that the antidiarrheal and antispasmodic activities of Lepidium sativum mediated through activation of K⁺ channels, and inhibition of muscarinic receptors, Ca⁺⁺ channels and PDE enzyme [62]. channels [61].
Clinical isolates of H. pylori were tested in vitro for susceptibility to ethanol extract of Lepidium sativum. The ethanol extract exerted antibacterial activity against H. pylori isolates. MIC value was 15-29 mm for concentrations of 100 000, 50 000 and 25 000µg/ml respectively [63].

Respiratory effects
The ethanolic extract of seeds of Lepidium sativum and its fractions (ethyl acetate, n-butanol and methanol) were tested for bronchodilatory effect against histamine and acetylcholine-induced acute bronchospasm in Guinea pigs. The ethanolic extract and its fractions exhibited significant protection against bronchospasm induced by histamine and acetylcholine, while, n-butanol fraction induced significant (p<0.001) protection comparable to ketotifen (1 mg/kg) and atropine sulphate (2 mg/kg [64]. The anti-asthmatic effect of Lepidium sativum seed powder (1 gm thrice a day orally) was investigated in patients of mild to moderate bronchial asthma. The respiratory functions (FVC, FEV1, FEF25-75% and MVV) were assessed using a spirometer prior to, and after 4 w of treatment. Efficacy of the drug in improving clinical symptoms and severity of asthmatic attacks was evaluated by interviewing the patient and by physical and hematological examination at the end of the treatment. Four weeks of treatment with the drug showed significant improvement in pulmonary functions and in clinical symptoms and severity of asthmatic attacks. None of the patients showed any adverse effect with Lepidium sativum [65].
The crude extract of Lepidium sativum inhibited carbachol (1 μM) and K + (80 mmol) induced contractions in Guinea pig tracheal ring strips, in a pattern similar to that of dicyclomine. The crude extract at 0.03 mg/ml produced a rightward parallel shift of carbachol curves, followed by a nonparallel shift at higher concentration (0.1 mg/ml), suppressing maximum response, similar to that caused by dicyclomine. Pretreatment of tissues with crude extract (0.1-0.3 mg/ml) shifted Ca ++ concentration-response curves to right, as produced by verapamil. The crude extract at low concentrations (0.03-0.1 mg/ml) caused a leftward shift of isoprenaline-induced inhibitory Ca ++ concentration-response curves, like that caused by rolipram, a phosphodiesterase inhibitor. Accordingly, the results indicated that the bronchodilatory effect of Lepidium sativum was mediated by anticholinergic, Ca ++
The activities of the optimized LSP extract of Lepidium sativum were tested in an in vivo endotoxin shock induced in mice with a single E. coli ip injection. Septic mice showed a substantial raise in the levels of TNF-α in plasma, whereas mice treated with Lepidium sativum polysaccharides (LSP) after E. coli injection showed considerable lower plasma levels of TNF-α (p< 0.05), which indicated the beneficial effects of LSP when administered to mice with endotoxin shock by diminishing the pro-inflammatory response [67].
Denaturation of tissue proteins is one of the well-documented causes of inflammatory and arthritis diseases. The protein denaturation bioassay was used for in vitro assessment of the anti-inflammatory property of methanol extract of Lepidium sativum seeds. the methanol extract of Lepidium sativum seeds exhibited a concentrationdependent inhibition of protein (albumin) denaturation throughout the concentration range from 25 to 1000 μg/ml [69].
The ethanolic extract of Lepidium sativum seeds was studied for antiinflammatory, antipyretic, and analgesic activities. The extract significantly inhibited carrageenan-induced paw edema in rats. It also significantly inhibited the yeast-induced hyperpyrexia in mice. The mean predrug rectal temperature in yeast-induced fevered mice was 37.13±0.05 °C. The administration of extract reduced the temperature to 36.86±0.04, 36.68±0.05 and 36.53±0.07 °C at 30, 90 and 150 min following the treatment respectively. Administration of Lepidium sativum extract (500 mg/kg) also significantly prolonged the hot plate reaction time. The ethanolic extract of Lepidium sativum seeds which possed anti-inflammatory, antipyretic and analgesic activities also exacerbated indomethacin-induced gastric mucosal damage. The coagulation studies showed a significant increase in fibrinogen level and an insignificant decrease in prothrombin time, confirming its coagulating property [15].
The antinociceptive effect of the aqueous extract of Lepidium sativum (20 mg/kg orally) was investigated using acetic acidinduced writhing test and hot plate test in mice. The aqueous extract showed significantly (p<0.05) analgesic activity evidenced by an increase in the reaction time by hot plate method and significant (p<0.05) reduction in acetic acid-induced writhings in mice with a maximum effect of 27% reduction [70].
In a clinical trial, the seeds (6 gm divided in two doses daily, orally) were evaluated for the management of osteoarthritis. The patients were subjected to the evaluation of cardinal sign and symptoms on the basis of scores according to their severity, frequency and duration before and after treatment. Seeds showed considerable improvements in cardinal signs and symptoms like pain in joints, swelling, stiffness, crepitus, tenderness and difficulty in movement (30% complete remission, 37.5% marked improvement, 25% moderate improvement, and only 7.5% didn't improve) [71].

Cardiovasular and diuretic effect
The ethanolic extract of the seeds of Lepidium sativum (10-20 mg/kg, iv) caused marked rise in blood pressure of anesthetized cats and dogs, with slight transient (0.5-1 min) respiratory stimulation. The extract was not potentiated or depress the pressor responses of adrenaline and carotid occlusion. The extract caused marked increase in the rate and force of auricular and ventricular movements of open chest cat heart preparation. The cardiac stimulatory effect was also observed on isolated rabbit auricles [72,73].
The antihypertensive effect of the aqueous extract of Lepidium sativum was studied in normotensive and spontaneously hypertensive rats. Daily oral administration of the aqueous extract (20 mg/kg for 3 w) caused a significant decrease in blood pressure (p<0.01) in hypertensive rats, with no significant change in normotensive rats during the period of treatment. The systolic blood pressure was decreased significantly from the 7 th day (p<0.05) to the end of treatment (p<0.01) in hypertensive rats. No significant changes were recorded on heart rate after the aqueous extract treatment in hypertensive and normotensive rats. The diuretic effect of the aqueous extract of Lepidium sativum was studied in normotensive and spontaneously hypertensive rats. The aqueous extract enhanced significantly the water excretion in normotensive rats (p<0.001) but not in hypertensive rats. Furthermore, oral administration of the aqueous extract at a dose of 20 mg/kg produced significant increase of urinary excretion of sodium (p<0.05), potassium (p<0.01) and chlorides (p<0.01) in normotensive rats. In spontaneously hypertensive rats, the aqueous extract administration induced significant increase of urinary elimination of sodium (p<0.01), potassium (p<0.001) and chlorides (p<0.001). Glomerular filtration rate showed a significant increase after oral administration of the aqueous extract in normal rats (p<0.001), while in hypertensive rats, no significant change was noted during the period of treatment [74].
The diuretic effect of aqueous and methanol extracts of the dried seeds of Lepidium sativum (orally, 50 and 100 mg/kg) was investigated in normal rats. Urine volume and the excretion of sodium were significantly increased by the two doses of aqueous and methanol extracts, while, potassium excretion was only increased by the aqueous extract at a dose of 100 mg/kg. The extracts caused no significant change in the conductivity and pH of urine [75].

Antioxidant activity
The antioxidant content and activity of the methanol extract of Lepidium sativum subsp spinescens was investigated in vitro. The extract contained high amounts of phenolic and flavonoid compounds and showed significant antioxidant activity [76].
The antioxidative effects of the ethanolic extract of Lepidium sativum shoot, leaf and stem were studied against DPPH, total glutathione Stransferase assay, reduced glutathione activity, reducing power (FeP 3+ P -FeP 2+ P transformation ability). High scavenging activity was noted in the shoot (12.19±02%) and least in stem (2.69±05%). The activity of the total glutathione S-transferase enzyme was more in seed (9600±56.3 μg/ml) than other plant parts. The reduced glutathione content of the ethanolic extracts of Lepidium sativum was more in leaf (9±0.2 μg/ml). In the reducing power assay, ethanolic extracts showed the most potent reducing ability [77].
The ethanol extract showed concentration-dependent antioxidant activity (0.146 to 18.75 mg/ml), the methanol extract was found to be a strong reducing agent and hence a strong antioxidant. Petroleum ether extract caused concentration-dependent antioxidant activity. The maximum increase in antioxidant activity was observed on changing the concentration from 3.125 mg/ml to 6.25 mg/ml [78].
Methanol and ethyl acetate extract of the seeds of Lepidium sativum showed significant antioxidant activity. Methanol extract exhibited antioxidant activities with ICR 50 Rof 925.22±0.02 ppm [27].
The seeds extract possessed good ferric reducing antioxidant power and DPPH radical scavenging activity with IC [50]:176.18 μg/ml. The antioxidant activity was also correlated to the total phenolic content of the seeds [79].

Anticancer effects
Cytotoxic effects of the plant extract on colon and endometrium cancer cells, in addition to human peripheral lymphocyte cells, were investigated in vitro by MTT and neutral red assays. Furthermore, the plant extract was investigated for necrotic effects by LDH assay; apoptotic activity by DNA ladder fragmentation, ELISA and acridine orange/ethidium bromide staining; and genotoxic effect by comet assay methods. The extract showed significant cytotoxic activity on colon and endometrium cancer cells in a concentration-dependent manner. Apoptotic activity and genotoxic effects were significantly increased, especially with 200 μg/ml concentrations at 48 h incubation [76].
The cytotoxic effects of hydro-alcoholic extracts of Lepidium sativum shoots (before and after flowering) were studied in K562 cell line as a model of chronic myeloid leukemia. The hydro-alcoholic extracts of Lepidium sativum prepared before and after flowering exhibited a dose and time-dependent cytotoxic effect on K562 cell line [80].
The cytotoxic activity of n-hexane, chloroform, ethyl acetate and methanol seeds extracts of Lepidium sativum was studied against human cancer cell lines such as human neuroblastoma cell line (IMR-32), colon cancer cell lines (HT-15 and HT-29) and lung cancer cell line A-549. The methanolic extract of Lepidium sativum exhibited a very high in vitro cytotoxic activity than that of standard mitomycin-C. Other three extracts showed no cytotoxicity [81].
The anticancer activity of Lepidium sativum seeds was investigated against HEp2 cells (human laryngeal carcinoma cells). The highest cytotoxic activity for the acetate ethyl extract (rich with Oglycosides) at 57μg/ml was recorded against HEp2 cells, cells proliferation were reduced 87%, this effect could be attributed to the apoptosis effects of the extract [82].
The ability of the extract to induce apoptosis and necrosis was investigated in the human breast cancer cell line MCF-7, compared to normal human skin fibroblasts. Apoptosis can be induced in both cells, by treatment with 25% and 50% extract, while necrosis was observed mainly after exposure to elevated extract concentrations (75%). DNA fragmentation was noted in both cells, in a time and dose-dependent manner. Both cells, at all extract concentrations, showed no significant differences in the number of living, dead, apoptotic, and necrotic cells [83].

The protective effects
The hepatoprotective effect of the Lepidium sativum ethanolic extract (150 and 300 mg/kg) was assessed by Dgalactosamine-induced/lipopolysaccharide liver damage model in rats. The extract possessed marked amelioration of hepatic injuries by attenuation of serum and lipid peroxidation. The extract also significantly down-regulated the D-GalN/lPS induced proinflammatory cytokines TNFα and IL-6 mRNA expression in a dosedependent fashion and up-regulated the IL-10. It also possessed hepatoprotective activity by down-regulating mRNA expression of iNOS and HOP -1 P . MPO activity and NF-κB DNA-binding effect were mitigated by the extract dose-dependently [84].
The hepatoprotective effect of ethanolic extract of Lepidium sativum seed (100, 200, and 400 mg/kg, once daily for 7 consecutive days) was studied against carbon tetrachloride-induced acute liver injury in rats. Pretreatment with the ethanolic seeds extracts significantly reduced the level of serum alanine transaminase, aspartate transaminase, alkaline phosphatase and bilirubin, which was increased significantly in carbon tetrachloride intoxicated group. Histological analysis of liver tissues in groups pretreated with the ethanolic seeds extracts showed mild necrosis and inflammation of the hepatocytes compared to the intoxicated group [85].
The hepatoprotective effect of methanolic extract (200 and 400 mg/kg) of Lepidium sativum was investigated in CClR 4R induced liver damage in rats. The extract caused significant reduction in biochemical parameters of the treated group. The severe fatty changes in the livers of untreated rats were significantly decreased in the extract-treated group [86].
The protective effects of chloroform extract of Lepidium sativum seed were investigated against oxidative stress and cytotoxicity induced by hydrogen peroxide (HR 2R OR 2R) in human liver cells (HepG2). Pre-exposure to the chloroform extract significantly attenuated the loss of cell viability up to 48% at 25 µg /ml concentration against HR 2ROR2R (LDR 50R value = 2.5 mM). The results also showed that the chloroform extract at 25 µg/ml concentration significantly inhibited the induction of reactive oxygen species generation (45%) and lipid peroxidation (56%), and increases the mitochondrial membrane potential (55%) and reduced glutathione levels (46%) [87].
The effects of aqueous extract of Lepidium sativum (200 and 400 mg/kg, po) against nephrotoxicity induced by doxorubicin was investigated in rats. The serum urea and creatinine levels in the doxorubicin treated group was significantly elevated (P<0.001), while it was significantly reduced in the Lepidium saivum aqueous extract treated groups. The renal antioxidant enzymes such as superoxide dismutase, catalase activities and level of reduced glutathione were declined and the level of malondialdehyde was elevated in the doxorubicin treated group. The activities of superoxide dismutase, catalase and level of reduced glutathione were elevated and level of malondialdehyde declined significantly in the Lepidium sativum plus doxorubicin. Histopathologically, Lepidium sativum markedly ameliorated doxorubicin-induced renal tubular necrosis [88].
The nephrocurative and nephroprotective activity of 200 mg/kg ethanolic extract of Lepidium sativum seed was investigated against cisplatin-induced nephrotoxicity. A single dose of cisplatin-induced loss in body weight, increase urine excretion and increased serum urea and creatinine. These effects were significantly recovered by 200 mg/kg in curative and protective groups. The malondialdehyde, superoxide dismutase, catalase and reduced glutathione level, were significantly elevated by 200 mg/kg in curative and protective groups. The level of brush border enzymes like Na + /K + ATPase, Ca ++ ATPase and Mg ++ The protective effect of 5% and 10% of Lepidium sativum seeds powder was studied in acute renal failure in male albino rats. The results showed that feeding acute renal failure with seeds powder at 5% and 10% in curative and protective groups improved the body weight gain, feed intake and feed efficiency ratio. The diet fortified at 5% and 10% seeds powder helped to improve blood lipid levels as well as reducing hazards on kidney and liver function compared with positive control groups (injected with cisplatin, which were considered as a major risk factor for renal failure disease). Histopathologically, kidney of rats in curative and protective groups fed on basal diet containing seeds powder at 10% showed mild proximal tubules cell necrosis and minimal interstitial inflammation [90].
ATPase were significantly reduced after singledose cisplatin injection and significantly elevated by treatment in curative and protective groups [89].

CNS activity
The effect of total alkaloid from seeds of Lepidium sativum (50,150 and 250 mg/kg, ip) on thiopental induced hypnosis (mice), locomotor activity (mice), motor coordination (mice), antianxiety (mice) and analgesic effect (rats) were investigated. The results revealed that the total alkaloid from seeds of Lepidium sativum considerably potentiated the thiopental induced hypnosis, decreased locomotor activity and motor coordination, and increased preference to plus-maze open arm. The total alkaloid from seeds of Lepidium sativum also increased the reaction time in caudal immersion and decreased the number of wriths in acetic acid-induced writhing [92].

Hypolipidemic effects
The total cholesterol, triacylglycerol and alanine transaminase (ALT) activity were increased significantly in the rats fed with high cholesterol diet as compared to the control group. Lepidium sativum reduced total cholesterol and ALT; however, higher dose (6 g/kg diet) was found better than lower dose (3 g/kg diet) in reducing serum triacylglycerol. Histopathological findings revealed that liver of cholesterol-treated rats showed varying degrees of vacuolar degeneration, fatty changes, fatty cysts, and lobular disarray. Livers of the Lepidium sativum-treated rats showed mild to moderate degree of recovery [93].
The effects of Lepidium sativum extract (20 mg/kg, orally for4 w) on the blood glucose and lipid profile were studied in hypercholesterolemic rats. Lepidium sativum treated group showed a significant lower value of plasma glucose 30%, cholesterol 22%, triglycerides 25%, LDL 23% and increase in HDL 32% [94].

Effect on fracture healing
The effect of Lepidium sativum seeds on fracture healing was investigated in fractures induced in the midshaft of the left femur of adult New Zealand White rabbits. The rabbits were fed soon after surgery with Lepidium sativum seeds mixed with their normal diet, whereas no seeds were given to the control group. X-rays of the induced fractures were taken at 6 and 12 w postoperatively to assess the healing of the fractures; furthermore the callus formation in millimeters at the longitudinal medial, longitudinal lateral and circumferential areas were also investigated. The test group had a statistically significant increase in the healing of fractures compared with the control group (p<0.001 for longitudinal medial/6 w, p<0.004 for circumferential, and p<0.043 for longitudinal medial/12 w) [95].

Side effects and toxicity
The administration of the ethanolic extract of Lepidium sativum seeds in single doses of 0.5 to 3.0g/kg did not produce any adverse effects or mortality in mice, whereas the animals treated with extract (100 mg/kg/day) for a period of 3 mo in drinking water showed no symptoms of toxicity except a statistically insignificant higher mortality rate [15].
The acute and subchronic toxicity of Lepidium sativum seeds was studied in adult Wistar rats. For the acute toxicity study, 0.5-5.0 g/kg bw of the seed powder was administered through diet to rats, and obvious symptoms of toxicity and mortality were monitored for 72 h. Acute doses of seed powder did not induce any symptoms of toxicity or mortality in rats. In subchronic toxicity study, 1.0-10.0% of the seed powder was administered to rats through diet for 14 w. Dietary feeding of seed powder did not produce any mortality, no significant changes in food intake, gain in body weight, the relative weight of organs and hematological parameters, macroscopic and microscopic changes in vital organs, were observed between experimental and control groups. Enzymes (LDH and SGPT) were within normal levels; however, the serum ALP and SGOT were significantly increased in male rats receiving 5.0 and 10 % of seed powder [96].
Lepidium sativum seed fed to Wistar albino rats at 2% (w/w) was non-toxic, 10% (w/w) was toxic but not fatal and 50% (w/w) of the diet for 6 w was lethal and caused depression in growth rate and entero-hepato-nephrotoxicity. Organ lesions were accompanied by anemia and leukopenia and were correlated with alterations in serum AST and ALT activities and concentrations of total protein, cholesterol, urea, and other serum constituents [97].
Water suspension of seed powder of Lepidium sativum (2, 4, 8 g/100/ml) in male rats for 3 and 6 w increased total serum protein, albumin was increased at the high dose group, and AST and GGT were within normal levels. ALT and ALK were significantly increased after 3 w in males receiving 2 and 4 g/kg, respectively. Liver parenchyma showed vascular dilation with congestion of central and portal veins in low doses (2 and 4 mg/ml) for 3 w, high doses given for 3 w showed periportal fibrosis and perivascular edema. Bile duct proliferation was a prominent feature in the specimens of Lepidium sativum treated animals [98].
The possible adverse effect of alcoholic extract of seeds of Lepidium sativum and Lepidium sativum seed oil on HepG2 cells, a human liver cell line was studied. Cells were exposed to 25 to 1000 μg/ml of alcoholic extract of seeds of Lepidium sativum and Lepidium sativum seed oil for 24 h. The results show that the extracts reduced cell viability and altered the cellular morphology in dose-dependent manner. They were also induced oxidative stress in dose-dependent manner indicated by decrease in glutathione level, catalase activity, and SOD activity and an increase in lipid peroxidation [99].
In the study of the acute and chronic effects of 15% of Lepidium sativum seed supplementation on gross organ morphology and histomorphometric indices in rats, it appeared that Lepidium sativum seed increased renal weight in the treated group. Histological analysis showed a significant change in the diameter of the Bowman's capsule, glomerulus and Bowman's space in the treated group. There was also an increase in glomerulosclerosis, metaplasia and hyperplasia in rats fed 15% of Lepidium sativum seed. In the proximal and distal tubules, there was a significant increase in tubular degeneration throughout the experiment. These results paired together show a significant toxic effect for rats fed 15% Lepidium sativum seed [56].
The effects of an aqueous Lepidium sativum seeds extract on the immune system and general health was studied in mice. An aqueous extract of ground Lepidium sativum seeds was orally gavaged to young adult male Swiss albino mice at a low dose (0.5 ml) and a high dose (1 ml) daily for 19-21 d. Results showed that Lepidium sativum seeds extract caused statistically significant increases in the mean white blood cell count and mean spleen weight in low dose group; however, for the high dose group, the increases tended to be more significant. The mean body weight for the high dose group showed clear increases compared to the control. The mean of white blood cell types, red blood cell, and platelet counts; mean hemoglobin concentration; mean total body gains; and weights of the organs (except for the spleen) were not significantly different for the low dose and high dose groups compared to the control [100].
One gram of Lepidium sativum seed powder/thrice a day for four weeks in asthmatic patients produced no adverse effect in all treated patients [65].
The oil extracted from the plant was edible and was used as a cooking medium, some people may experience symptoms of indigestion due to its use. However, consuming of large quantities of the plant caused digestive difficulties in some people. Furthermore, it contained goitrogens that prevent iodine absorption in thyroids and can lead to hypothyroidism. It should be avoided by patients of hypothyroidism.
It was an abortifacient; pregnant women should avoid taking the plant in any form because it induce uterine contractions and triggered spontaneous abortion [24][25].

CONCLUSION
The current review discussed the chemical constituents, pharmacological effects and therapeutic importance of Lepidium sativum as a promising medicinal plant with wide range of pharmacological activities which could be utilized in several medical applications because of its effectiveness and safety.

ACKNOWLEDGMENT
I acknowledged the dean of Thi qar college of medicine for his scientific support.

AUTHORS CONTRIBUTIONS
All the author have contributed equally

CONFLICTS OF INTERESTS
There is no conflicts of interest. I am, alone responsible for the content and writing of this article.