Pharmacology & Toxicology

International Journal of Pharmacology & Toxicology / 5(2), 2015,76-81.

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THE CHEMICAL CONSTITUENTS AND PHARMACOLOGICAL EFFECTS OF CAPSELLA BURSA-PASTORIS- A REVIEW Ali Esmail Al-Snafi Department of Pharmacology, College of Medicine, Thiqar University, Nasiriyah, PO Box 42, Iraq.

ABSTRACT Herbal medicine is the oldest form of healthcare known to mankind. Herbs had been used by all cultures throughout history. The World Health Organization (WHO) estimates that 80 percent of the world populations presently use herbal medicine for some aspect of primary health care. Capsella bursa-pastoris is one of the plants commonly used in the traditional medicine in many countries. It contained a wide range of chemicals including flavonoids, polypeptides, choline, acetylcholine, histamine, tyramine, fatty acids, sterols, organic acids, amino acids, sulforaphane, many trace elements, vitamins and many other compounds. Capsella bursa-pastoris exerted antimicrobial, anti-inflammatory, antioxidant, cardiovascular, reproductive, anticancer, hepato-protective, sedative and other pharmacological effects. The present review will highlight the chemical constituents and the pharmacological and therapeutic effects of Capsella bursa-pastoris. Keywords: Capsella bursa-pastoris, Chemical constituents, pharmacology. INTRODUCTION Capsella bursa-pastoris is one of the plants commonly used in the traditional medicine for many purposes. It contained a wide range of chemicals including flavonoids, polypeptides, choline, acetylcholine, histamine, tyramine, fatty acids, sterols, organic acids, amino acids, sulforaphane, many trace elements, vitamins and many other compounds. Capsella bursa-pastoris exerted antimicrobial, anti-inflammatory, antioxidant, cardiovascular, reproductive, anticancer, hepatoprotective, sedative and other pharmacological effects Common names Arabic: Madakat el Raee, Kess el Raee, Sharabat el Raee, Gezdan el Raee, Karmala; English: Shepherd's Bag, Shepherd's Scrip, Shepherd's Sprout, Lady's Purse, Witches' Pouches, Rattle Pouches, Case-weed, PickPocket, Pick-Purse, Blindweed, Pepper-and-Salt, Poor Man's Parmacettie, Sanguinary, Mother's Heart and Clappedepouch; French: Bourse de Pasteur; German: Hirtentasche [1].

Family: Cruciferae; Brassicaceae Distribution Capsella bursa-pastoris is native in different parts of the world, including Cyprus, Europe, Saudi Arabia, Turkey, Pakistan, India, Iran, Iraq, Azarbayjan, China and many other places in Asia. It is also found in North African, central America and Eastern European [24]. Traditional uses The plant was used medicinally as haemostatic, diuretic and antipyretic in China and Japan for many centuries [5]. The whole plant was used to treat edema caused by nephritis, odynuria, hemafecia, menorrhagia, chyluria and hypertension [6]. The leaves and roots of the plant were used as an edible vegetable, eaten raw or cooked in some countries [7-8]. A tea made from the whole plant was used as antiscorbutic, astringent, diuretic, emmenagogue, haemostatic, hypotensive, oxytocic,

Corresponding Author:-Ali Esmail Al-Snafi Email:[email protected]

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stimulant, vaso-constrictor and vulnerary. A tea made from the dried herb was considered to be a sovereign remedy against haemorrhages of all kinds, the stomach, the lungs, the uterus and more especially the kidneys. The plant has been ranked 7th amongst 250 potential antifertility plants in China. A homeopathic remedy is made from the fresh plant to be used in the treatment of nose bleeds and urinary calculus [9]. Part used: Whole plant was used medicinally. Chemical constituents The aerial parts contained flavonoids, polypeptides, choline, acetylcholine, histamine and tyramine [10].The plant also contained minerals, vitamin A, ascorbic acid, proteins, linoleic acid and ω3 polyunsaturated fatty acid[7,11].Leaves (100g) contained 280 calories, protein: 35.6 g, fat: 4.2 g, carbohydrate: 44.1 g; fiber: 10.2 g, ash: 16.1 g, vitamins A 21949 mg, thiamine (B1) 2.12 mg, riboflavin (B2) 1.44 mg, niacin 3.4 mg, vitamin B6: 0 mg and vitamin C 305 mg [12]. The edible parts of Capsella bursa-pastoris contained the following minerals and trace elements (mg/kg): Cu 0.70±0.07, Pb 6.32±1.12, Zn 5.48±1.24, Mn 4.50±1.56, Co 0.15±0.02, K 224.4±18.66, Fe 44.36±4.47 Ca 2.396±152.4 and Na 2.90±0.58 [12-13]. The fatty acid composition of the seeds and roots oils of Capsella bursa-pastoris included (%): azelaic acid 1.802 and 10.024 palmitic acid 18.168 and 44.076, stearic acid 9.874 and 9.570 oleic acid 22.863 and 16.101, linoleic acid 20.589 and 13.402, linolenic acid 12.197 and 6.826, arachidonic acid 3.370 and 0 , and 11-eikozenoic acid 11.136 and 0 % respectively. In comparison of the fixed oil composition of the seeds and roots of the Capsella bursa-pastoris, it was found that the seed oil was rich in unsaturated fatty acids (oleic linoleic and linolenic) whereas the root oil was rich in palmitic acid [14]. However, Grossoet al., mentioned that the free fatty acids isolated (as methyl esters) from C. bursapastoris were included (mg/Kg of dry plant) dodecanoic acid (lauric acid)b 5.66±1.17, tetradecanoic acid (myristic acid) 29.63±5.79, pentadecanoic acid 18.05±3.06, (Z)-9hexadecenoic acid (palmitoleic acid) 23.29±0.49, (Z)-7hexadecenoic acid 22.97±4.27, hexadecanoic acid (palmitic acid) 284.48±41.06, 9,10-(Z)-methylenehexadecanoic acid 17.59±2.18, heptadecanoic acid 7.11±1.60, (Z)-9.12-octadecadienoic acid (linoleic acid) 20.09±4.35, (Z)-9-octadecenoic acid (oleic acid) 53.03±9.99, (Z)-6-octadecenoic acid 9.00±0.08, Octadecanoic acid (stearic acid) 53.20±0.68, and eicosanoic acid (arachidic acid) 2.52±0.33 [15]. The phytosterol compounds identified in dichloromethane extracts of C. bursa-pastoris were included cholesterol, campesterol, , stigmasterol, βsitosterol, cholest-5-en-3-one, ergosta-4,6,8 [14], 22-

tetraen-3-one, lupeol, stigmasta-3,5-dien-7-one, stigmasta4-en-3-one in addition to unidentified phytosterols [15]. Nine flavonoids were isolated from the whole plant of Capsella bursa-pastoris, their structures were identified as tricin, kaempferol, quercetin, kaempferol-7O-α-Lrhamnopyranoside, quercetin-3-O-β-D– glucopyranoside, quercetin-6-C-β-D-glucopyranoside, kaempferol-3-O-β-D-glucopyranosyl-7-O-α-Lrhamnopyranoside, quercetin-3-O-β-Dglucopyranosyl- 7O-α-L-rhamnopyranoside and kaempferol-3-O-rutinoside [6,16]. The amounts of some of these flavonoids were determined in the methanol and methanol/water extraction of C. bursa-pastoris(mg/kg of dry plant) including quercetin-6-C-glucoside 793.90±8.80 and 564.32±8.09, quercetin-3-O-glucoside 426.26±1.01 and 1241.25±37.61, kaempferol-3-O-rutinoside 2314.61±11.59 and 2179.57±67.68, quercetin 16.36±0.59 110.86±15.69 and kaempferol 16.01±0.12 and 130.41±12.27 respectively [15]. Capsella bursa-pastoris also contained isothiocyanate compound, sulforaphane [17]. Organic acid composition of C. bursa-pastoris (mg/kg of dry plant) included oxalic 2416.98±405.50, citric 27408.80±4161.68, malic 68288.82±11217.03, quinic 95628.00±15827.51, shikimic 8.02±1.15 and fumaric 3540.02±546.01 [15]. Two peptides were isolated from Capsella bursapastoris ,named shepherin I and shepherin II, consisted of 28 and 38 amino acids, respectively, and wee glycine- and histidine-rich peptides. Shepherin I and shepherin II have 67.9% and 65.8% (mol/mol) glycine, respectively, and 28.6% and 21.1% (mol/mol) histidine, respectively. Both shepherins have a Gly-Gly-His motif [18]. The methanol and methanol/water extraction of C. bursa-pastoris resulted in identification of total amino acid 1823.25±71.38 and 2550.56±129.04 (μg/kg of dry plant) respectively. Eighteen amino acids were extracted from methanol and methanol/water extracts including (μg/kg of dry plant, respectively) glutamic acid 0 and trace, asparagine 0 and 3.77±0.47, serine 4.01±0.43 and 1.39±0.11, threonine 4.93±0.61 and 0, glycine 12.23±0.65 and 9.17±0.63, alanine trace and trace, valine 23.71±1.32 and 11.15±0.30, proline 80.51±5.33 and 36.10±4.22, arginine 1054.57±44.11 and 1296.55±77.89, isoleucine 23.24±2.10 and 0, leucine 14.58±0.72 and 7.42±0.83, tryptophan 0 and 2.51±0.38, phenylalanine 6.51±0.55 and 174.83±6.41, cysteine 86.24±3.30 and 149.09±6.07, qrnitine 8.19±0.75 and 3.31±0.30, lysine trace and 12.49±0.71, histidine 6.05±0.58 and 54.03±3.87 and tyrosine 522.78±45.88 and 796.97±29.40 (1,15). PHARMACOLOGICAL EFFECTS Antimicrobial effects Soxhlet benzene extracts of Capsella bursapastoris, exerted an effective antibacterial effects. Alkaloids and flavonoids of Capsella gave the highest

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antibiotic potencies and had the broadest antimicrobial spectra [19]. Antibacterial activity of ethanolic and aqueous extracts of Capsella bursa-pastoris were carried out against eight different species of bacteria, Gram-positive Staphylococcus aureus and Enterococcus fecalis and Gram-negative Escherichia coli, Proteus vulgaris, Serratiamar cescens, Acinitobacter bumani, Klebsiella pneumoniae and Pseudomonas aeruginosa. It showed antibacterial activity only against gram-negative bacteria. The ethanolic and aqueous extract showed different activities; the aqueous extract (hot) showed the same or greater activity than the ethanolic extract by disc diffusion. Hot aqueous extract in a concentration of 2000 and 3000 μg/ml inhibited the growth of five gram negative pathogens in almost similar pattern. Ethanolic extract was active only against Ps. aeruginosa and K. pneumoniae. All isolates were tested by different concentration of sub-MIC of aqueous and ethanolic extracts, these concentrations inhibited or omitted the ability of those isolates to produce virulence factors (DNase, haemolysin production and lipase production) [20]. C. bursa-pastoris ethanolic extract showed good antibacterial activity against six oral pathogens [Streptococcus mutans (PTCC 1683), S. sanguis (PTCC 1449), Actinomyces viscosus (PTCC 1202), Enterococcus faecalis (ATCC 29212) as oral pathogens and Staphylococcus aureus(ATCC 25923) and Escherichia coli (ATCC 29922)]. No strain showed resistance against this extract [21]. The effect of Capsella bursa pastoris alcoholic extract was assayed on different stages of bacterial growth (E. coli, Pseudomonas aerogenesis, Staphylococcus aureusand Bacillus cereus). The results showed that extract caused significant changes in the bacterial growth in different concentrations (2). A sulforaphane-containing solution (SCS) isolated from Capsella bursa-pastoris inhibited vancomycin-resistant enterococci (VRE) and Bacillus anthracis. The minimal inhibitory concentration was 250 µg/ml for VRE and 1,000 µg/ml for B. anthracis (17). Two novel antimicrobial peptides were isolated and characterized from the roots of Capsella bursapastoris. These antimicrobial peptides, named shepherin I and shepherin II, consist of 28 and 38 amino acids, respectively, and were glycine- and histidine-rich peptides. Shepherin I and shepherin II have 67.9% and 65.8% (mol/mol) glycine, respectively, and 28.6% and 21.1% (mol/mol) histidine, respectively. Both shepherins have a Gly-Gly-His motif. These peptides exhibit antimicrobial activity against Gram-negative bacteria and fungi [18]. The antibacterial potential of Capsellabursapastoris methanol, methanol/water and dichloromethane extracts were screened for activity against five Grampositive (Staphylococcus aureus, Staphylococcus epidermidis, Micrococcus luteus, Enterococcus faecalis

and Bacillus cereus), and four Gram-negative (Proteus mirabilis, Escherichia coli, Pseudomonas aeruginosa and Salmonella typhimurium). The MICs obtained for methanol and methanol/water extracts were lower than those of dichloromethane. In addition, Gram-positive bacteria were more susceptible than Gram-negative ones [15]. Anticancer effects An inhibitory effect of the extracts of the herb on Ehrlich solid tumour in mice was found to be due to the fumaric acid [10].The water, ethanol and methanol extracts of C. bursa-pastoris caused 42.9, 29.5 and 42.9% tumor inhibition [22]. The effects of methanol extracts of Capsella bursa-pastoris (MECB) was evaluated on the cell growth and apoptosis of HSC-2 human oral cancer cells. MECB caused growth inhibition and induction of apoptosis in a concentration-dependent manner in HSC-2 cells. A marked reduction in specificity protein 1 (Sp1) expression following treatment with MECB was also observed. The down regulation of Sp1 by siRNA resulted in growth inhibition and a reduction of total poly (ADPribose) polymerase (PARP) expression. In addition MECB was significantly increased Bak expression levels and decreased Mcl-1 expression levels [23]. The treatment of ICR mice with ip injections (0.14 g/kg/ day) of the extract of Capsella bursa-pastoris herb caused 50 to 80% inhibition of the solid growth of Ehrlich tumor cells that had been inoculated into the sc tissue of the animals. The tumor lumps in the treated mice showed multifocal necroses and the infiltration of host fibrous tissue cells. An acidic substance was isolated in crystalline form from the herb extract as antitumor agent. This acidic substance was identified as fumanic acid and was effective in inhibiting the growth of Ehrlich Solid tumor at a dose of 10 mg/kg/day. The 50% lethal dose (ip) of this acid was 266 mg/kg [24]. Fumaric acid, isolated as the active component of Capsella bursa-pastoris was found to reduce markedly the growth and viability of Ehrlich, MH134, and L1210 mouse tumor cells in culture at concentration of 0.3-1.2 mg/ml. In contrast, fumaric acid at these concentrations in the culture medium had no deleterious effect on the monolayer development of mouse and chick embryo cells but exhibited activity to enhance the recovery of the cells from the toxic effects of mitomycin C, aflatoxin B1, Nmethyl-N'-nitro-N-nitrosoguanidine, and potassium 1methyl-7-[2-(5-nitro-2-furyl) vinyl]-4-oxo-1,4-dihydro1,8-naphthyridine-3-carboxylate (25). Anti-inflammatory effects The plant induced anti-inflammatory activity in carrageenan-induced and dextran-induced rat paw oedema. It also reduced capillary permeability in guinea-pig induced by histamine and serotonin. In addition, it

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possessed anti-ulcer activity in rats following intraperitoneal injection. The extract did not affect gastric secretion, but accelerated recovery from stress-induced ulcers [5, 26]. The anti-inflammatory and antibacterial properties of a sulforaphane-containing solution (SCS) isolated from shepherd's purse (Capsella bursa-pastoris) had significant anti-inflammatory activity indicated by the decreased levels of nitric oxide (NO), cytokines (interleukin 1β [IL-1β], IL-6, and IL-10), and prostaglandin E2 (PGE2) in lipopolysaccharide-stimulated RAW 264.7 murine macrophages. SCS also decreased the inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2) levels, which confirmed the anti-inflammatory activity of SCS [17]. Effects on smooth muscles Evaluation of acetylcholinesterase inhibition of the Capsella bursa-pastoris extracts revealed that these extracts were moderate acetyl cholinesterase inhibitors (15). The plant induced stimulatory action on the small intestine in the guinea-pig, the activity which unaffected by atropine and diphenhydramine, but were inhibited by papaverine [27]. The extract of dried or green plant causes strong contraction of the small intestines and uterus of guinea pigs. A quaternary ammonium salt has been isolated from the herb which is reported to be responsible for its pharmacological activity [10]. A purified substance from an alcohol extract of Capsella bursa-pastoris exerted contractile activity on the rat uterus which was similar to that of oxytocin and had some characteristics of a polypeptide [5]. Water extracts (infusions) from a group of medicinal plants including Capsella bursa-pastoris enhanced the uterine tonus in a series of experiments on isolated rabbit and guinea pig uterine horn [28]. The plant was used in the treatment of menorrhagia and metrorrhagia, which seem to be mediated through an increased contraction of smooth muscles and uteromimitic effect. As a tea-like infusion, the recommended dose is 2 to 4 g in 150 ml of water after boiling for 15 minutes. This solution should be taken two, three or four times a day [4]. Effects on fertility Capsella bursa-pastoris, dried and ground, added at rates of 20 and 40% to the stock diet of male and female mice, showed that both materials, at the 40% level impeded ovulation and produced temporary infertility in males and females [29]. Antioxidant effects The methanolic and aqueous extracts which contained many flavonoids exerted an antioxidant activity against DPPH radicals, peroxyl radicals, hydroxyl radicals, and hydrogen peroxide [16]. Evaluation of

antioxidant activity of Capsella bursa-pastoris extracts revealed that these extracts are efficient free radical scavengers [15]. Cardiovascular effects The plant increased coronary blood flow in dogs following intra-arterial administration, and caused a slight inhibitory effect on ouabain-induced ventricular fibrillation in the rat following intraperitoneal injection, together with a negative chronotropic effect. It caused negative chronotropic and inotropic actions on the isolated hearts of guinea-pig and rabbit [27]. Young leaves contained hesperidin and rutin, which reduced permeability of blood vessel walls in white mice [10]. Effects on psoriasis and multiple sclerosis Fumarates (found abundantly in Shepherd’s purse) were evaluated for improving psoriasis and multiple sclerosis by inducing type II dendritic cells. In mice, fumarates generate type II DCs that induce IL-4producing Th2 cells in vitro and in vivo and protect mice from experimental autoimmune encephalomyelitis. Type II DCs was resulted from fumarate-induced glutathione (GSH) depletion, followed by increased hemoxygenase-1 (HO-1) expression and impaired STAT1 phosphorylation. Induced HO-1 is cleaved, whereupon the N-terminal fragment of HO-1 translocates into the nucleus and interacts with AP-1 and NF-κB sites of the IL-23p19 promoter [30]. Hepatoprotective effects Capsella bursa-pastoris showed hepatoprotective activity in hepato toxicity induced by CCl4 in rats. The serum levels of SGOT and bilirubin in the animals treated by Capsella bursa–pastoris (aerial parts) crude extract showed significant decreases by (26.9 and 31.7 %) respectively, at a dose of 500 mg/kg body weight (p