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Pharmaceutical Biology

ISSN: 1388-0209 (Print) 1744-5116 (Online) Journal homepage: http://www.tandfonline.com/loi/iphb20

Phytochemical and pharmacological potential of


Medicago sativa: A review

Kundan Singh Bora & Anupam Sharma

To cite this article: Kundan Singh Bora & Anupam Sharma (2011) Phytochemical and
pharmacological potential of Medicago sativa: A review, Pharmaceutical Biology, 49:2, 211-220,
DOI: 10.3109/13880209.2010.504732

To link to this article: http://dx.doi.org/10.3109/13880209.2010.504732

Published online: 25 Oct 2010.

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Pharmaceutical Biology, 2011; 49(2): 211220
2011 Informa Healthcare USA, Inc.
ISSN 1388-0209 print/ISSN 1744-5116 online
DOI: 10.3109/13880209.2010.504732

REVIEW ARTICLE

Phytochemical and pharmacological potential of


Medicago sativa: A review
Kundan Singh Bora1 and Anupam Sharma2
1
L.R. Institute of Pharmacy, Solan, Himachal Pradesh, India, and 2University Institute of Pharmaceutical Sciences,
Panjab University, Chandigarh, India

Abstract
Context: Many herbal remedies have so far been employed for the treatment and management of various ailments
since the beginning of human civilization. Medicago is an extensive genus of the family Leguminosae, comprising
about 83 different species. Medicago sativa (Linn.) has long been used as traditional herbal medicine in China, Iraq,
Turkey, India and America for the treatment of a variety of ailments.
Objectives: The aim of this review was to collect all available scientific literature published and combine it into this
review. The present review comprises the ethnopharmacological, phytochemical and therapeutic potential of
M.sativa.
Methods: The present review includes 117 references compiled from major databases as Chemical Abstracts, Science
Direct, SciFinder, PubMed, Dr. Dukes Phytochemical and Ethnobotany, CIMER, and InteliHealth.
Results: An exhaustive survey of literature revealed that saponins, flavonoids, phytoestrogens, coumarins, alkaloids,
amino acids, phytosterols, vitamins, digestive enzymes and terpenes constitute major classes of phytoconstituents
of this plant. Pharmacological reports revealed that it is used as neuroprotective, hypocholesterolemic, antioxidant,
antiulcer, antimicrobial, hypolipidemic, estrogenic, and in the treatment of atherosclerosis, heart disease, stroke,
cancer, diabetes and menopausal symptoms in women.
Conclusion: M. sativa seems to hold great potential for in-depth investigation for various biological activities,
especially their effects on central nervous and cardiovascular system. Through this review, the authors hope to attract
the attention of natural product researchers throughout the world to focus on the unexplored potential of M. sativa,
and it may be useful in developing new formulations with more therapeutic value.
Keywords: Antidiabetic, antiatherosclerotic, hypocholesterolemic, Medicago sativa, neuroprotective

Introduction used in India and Malaysia as an antidote for insect and


The use of plants for medicines or tonic properties goes snake bites and mental derangement. The utility of plants
back to prehistoric times and has attracted the interest as therapeutic agents in traditional medicine system is
of scientists for centuries. The Vedas give the earliest still prevalent today. For example, the Middle Eastern
written record about the science of healing. The refer- civilization developed the Greco-Arabic system of medi-
ence to medicinal plant is also found in the Ebers papy- cine (Unani system of medicine), which is practiced in
rus (16th century B.C.) which lists in detail over 7000 the Indian sub-continent. The Ayurvedic and Sidha sys-
herbal remedies, for example poppy, castor oil, caraway tem of medicines were contributed by Indians. All these
etc. The Indians were the first to use chaulmoogra fruits systems procure more than 80% of their medicaments
for its antileprotic activity. The Brazilians employed from plants (Bhavna etal., 2007).
Ipecacuanha for the treatment of dysentery and diar- Medicago sativa Linn. (Leguminosae), commonly
rhea. The root of Rauwolfia serpentine (Benth.), an indig- known as the father of all foods (al-fal-fa), is a peren-
enous plant, has since time immemorial been widely nial herbaceous leguminous plant species that originated

Address for Correspondence: Kundan Singh Bora, L.R. Institute of Pharmacy, Solan, Himachal Pradesh 173212, India. Tel.: +91-1792 252854.
Fax: +91-1792 252851. E-mail: kundanresearch1381@gmail.com
(Received 11 June 2010; revised 24 June 2010; accepted 24 June 2010)

211
212 Kundan Singh Bora, and Anupam Sharma
in Asia (Ehsanpour & Razavizadeh, 2005; Duke, 1985; found in Argentina (primarily grazed), Australia, South
BHMA, 1996). This is the most ancient plant, cultivated Africa, and the Middle East (FAO, 2006). Within the USA,
throughout the world as a fodder plant. In America, M. the leading M. sativa growing states are California, South
sativa has been extensively cultivated since the arrival of Dakota, and Wisconsin. The upper Midwestern states
Europeans. M. sativa has been grown for a variety of pur- account for about 50% of US production, the Northeastern
poses such as soil improvement, animal feed and medici- states 10%, the Western states 40%, and the Southeastern
nal uses (Steppler, 1987). states almost none. M. sativa has a wide range of adap-
M. sativa has a long tradition of use as Ayurvedic and tation and can be grown from very cold northern plains
homoeopathic medicine in central nervous and digestive to high mountain valleys, from rich temperate agricul-
system disorders, and for the treatment of various other tural regions to Mediterranean climates and searing hot
ailments. However, only limited research has been con- deserts.
ducted on this plant species. The present review empha-
sizes the traditional uses and phytopharmacological
potential of M. sativa. Additionally, sporadic pharma- Ethnopharmacological uses
cological work has so far been carried out to prove its Traditionally, M. sativa is used to improve the memory, to
traditional claims. Through this review, the authors hope cure kidney pain, cough, sore muscles, as a rejuvenator,
to attract the attention of natural product researchers antidiabetic, antioxidant, anti-inflammatory, antifungal,
throughout the world to focus on the unexplored poten- anti-asthmatic, antimicrobial, diuretic, galactagogue
tial of M. sativa. No review so far has been compiled on and in central nervous system (CNS) disorders (Finkler,
this species, and therefore it was considered important 1985; BHMA, 1996; Inamul, 2004; DerMarderosian etal.,
to take stock of what has been done in the past, in order 2005). M. sativa has a long tradition of use as Ayurvedic
to provide a solid foundation and direction to any future and homoeopathic medicine in CNS disorders (Inamul,
research that may be conducted on this plant. 2004). M. sativa has been used by the Chinese since the
sixth century to treat kidney stones, fever, gravel, dysuria
Scientific classifications (Heywood & Ball, 1968) and to relieve fluid retention and swelling. Ancient Indian
Ayurvedic physicians used M. sativa to treat ulcers,
Kingdom: Plantae; Division: Magnoliophyta; Class: arthritis pain and fluid retention. In Mexico M.sativa is
Magnoliopsida; Order: Fabales; Family: Fabaceae; believed to improve the memory, to cure sore muscles
Subfamily: Faboideae; Tribe: Trifolieae; Genus: Medicago; and inflammation. Early Americans used M. sativa to
Species: sativa; Binomial name: M. sativa Linn. treat arthritis, boils, cancer, scurvy, and urinary and
bowel problems. In Iraq M. sativa is used in arthritis. In
Description: general morphology Turkey it is used as cardiotonic and to treat scurvy and
arthritis (Michael etal., 2007; Finkler, 1985; Inamul, 2004;
M. sativa is a cool season perennial legume living from DerMarderosian etal., 2005).
three to twelve years, depending on variety and climate. Moreover, it is considered beneficial in bladder dis-
The general morphology of M. sativa plant was consid- orders, blood clotting disorders, boils, cough, diuresis,
ered by Teuber and Brick (1988), and Barnes and Sheaffer gastrointestinal tract disorders, breast cancer, cervical
(1995). The mature M. sativa plant is characterized by a cancer, kidney disorders, prostate disorders, appetite
strong taproot. This taproot may eventually surpass 6 m stimulation, inflammation, increasing breast milk,
or more in length with several to many lateral roots con- asthma, indigestion, insect bites, jaundice, menopausal
nected at the crown when M. sativa is grown in deep, well symptoms, allergies, increasing excretion of neutral ste-
drained, moist soils. The crown, a complex structure near roids and bile acids in fecal matter, nutritional support,
the soil surface, has perennial meristem activity, produc- stomach ulcers, skin damage from radiation, galact-
ing buds that develop into stems. Tri- or multi-foliolate agogue, increasing peristaltic action of the stomach and
leaves form alternately on the stem, and secondary and bowels, thrombocytopenic purpura, uterine stimulant,
tertiary stems can develop from leaf axils. A plant in a rheumatoid arthritis, scurvy, vitamin supplementation
typical forage production field has between 5 and 15 (vitamins A, C, E, K) and wound healing (Gray & Flatt,
stems and can reach nearly 1 m in height. Flowers vary in 1997a, 1997b; BHMA, 1996; DerMarderosian etal., 2005;
color yet purple, variegated, yellow, cream and white are Swanston etal., 1990).
the most common. After pollination, these flowers most
commonly produce spiral-shaped seed pods.
Phytochemical reports
M. sativa has been reported to contain a variety of
Worldwide production phytochemicals. It has following different classes of
M. sativa is the most cultivated legume in the world. phytoconstituents.
Worldwide production was around 436 million tons Alkaloids: asparagines, trigoneline, stachydrine,
(436000000 metric tons) in 2006. The USA is the largest l-homostachydrine (Duke, 1985; Mills, 1994; Tamsyn
M. sativa producer in the world, but considerable area is etal., 2009). Amino acids: medicanine, lysine, arginine,
 Pharmaceutical Biology
Medicago sativa: A review 213
histidine, tyrosine, phenylalanine, methionine, aspartic glucopyranosyl(1 2)- -d-glucopyranoside]
acid, glutamic acid, asparagine, serine, alanine, threo- medicagenic acid, 3-O-[-d-glucopyranosyl(12)--d-
nine (Worthington & Breskin, 1983; Fushiya etal., 1984; glucopyranosyl(12)--d-g lucopyranosyl]-28--d-
Lihu & Pedak, 1979; Mego & Erdelsky, 1977). Carotene glucopyranoside medicagenate, 3-O-[-d-glucuronopy-
(Gupta et al., 1981). Coumarins: myrsellinol, scopole- ranosylmethylester]-28-O-[-d-xylopyranosyl(14)--l-
tin, esculetin, 4-coumaric acid (Duke, 1985; El-Khrisy rhamnopyranosyl(12)--l-arabinopyranoside]
et al., 1994; Orr et al., 1993). Digestive enzymes (Duke, medicagenate, 3-O-[-l-rhamnopyranosyl(12)--d-
1985). Enzymes: isoflavone reductase, vestitone galactopyranosyl(12)--d-glucuronopyranosyl]-21-
reductase, iminopeptidase, and two aminopeptidases O--l-rhamnopyranoside soyasapogenol A, 3-O-[-d-
(Xiaoqiang etal., 2006; Shao etal., 2007; Biagioni etal., glucopyranosyl(12)--d-glucopyranosyl(12)
1990). Flavonoids: quercetin, myricetin, luteolin, api- glucopyranosyl]-28-O-[-d-xylopyranosyl(14)--l-
genin, chrysoeriol, tricin, 4'-O-[2'-O-E-feruloyl-O-- rhamnopyranosyl(12)--l-arabinopyranoside] medica-
glucuronopyranosyl(12)-O--lucuronopyranoside] genate,3-O-[-d-glucopyranosyl(12)--d-glucopyranosyl
apigenin,7-O--glucuronopyranosyl-4'-O-[2'-O-E-feruloyl- (1 2)glucopyranosyl]-28-O-{ -d-xylopyranosyl
O--glucuronopyranosyl(12)-O--glucuronopyra- (1 4)-[ -d-apiofuranosyl-(13)]- -l-rhamno
noside] apigenin, 7-O--glucuronopyranosyl-4'-O-[2'- pyranosyl(12)--l-arabinopyranoside} medicagenate,
O-p-E-coumaroyl-O--glucuronopyranosyl(12)-O-- 3-O-[-d-glucopyranosyl(12)--d-glucopyranosyl(12)--
glucuronopyranoside] apigenin, 7-O-{2-O-E-feruloyl- d-glucopyranosyl]-28-O-[-d-xylopyranosyl(14)--l-
[-glucuronopyranosyl(13)]-O--lucuronopyranosyl rhamnopyranosyl(12)--l-arabinopyranoside]zahnic
(12)-O--glucurono-pyranoside} apigenin, O-glycosyl acid, 3-O-[-d-glucopyranosyl(12)--d-glucopyranosyl
transferases, medicarpin, coumestrol, sativan, vestitol, (12)--d-glucopyranosyl]-28-O-{-d-xylopyra
formononetin (Bickhoff et al., 1964; Stochmal et al., nosyl(14)-[-d-apiofuranoside-(13)]--l-rhamno
2001; Kowalska et al., 2007; Stochmal & Oleszek, 2007; pyranosyl(12)--l-arabinopyranoside}zahnic acid, 3-
Parry & Edwards, 1994; Dutu etal., 2002; Dixon & Steele, O-[-d-galactopyranosyl(12)--d-glucuronopyranosyl]-
1999; Sumner etal., 1996; Piretti etal., 1982). Minerals: 28-O--d-glucopyranoside bayogenin, 3-O-[-l-rham-
Ca, K, P, Mg, Fe, Zn, Cu, Al, B, Cr, Co, Mn, Mo, Se, Si, Na, nopyranosyl(12)--d-galactopyranosyl(12)--d-
Sn (Worthington & Breskin, 1983; Potgieter, 2005). glucuronopyranoside] soyasapogenol E (Bialyetal., 1999),
Non-protein amino acids: l-canaverin (Albourine et al., 3-O-[-d-glucopyranosyl (1-2)--d-glucopyranosyl(1-2)-
1991; Tamsyn et al., 2009). Organic acids: citrate, malate, -d-glucopyranosyl]-2,3,16-trihydroxyolean-12-
malonate, succinate, fumarate, lactate, benzoate (Francoise en-23,28-dioic acid-23-O--l-arabinopyranosyl-28-O-
et al., 1991; Tamsyn et al., 2009). Phenolic compounds: [-d-apiofuranosyl(1-3)--d-xylopyranosyl(14)-
p-hydroxybenzoic acid, vanillic acid, p-coumaric acid, -l-rhamnopyranosyl(1-2)- -l-arabinoside]
ferulic acids, salicylic acid, sinapic acids, caffeic acid, (Oleszek et al., 1992), 28-O-[-d-xylopyranosyl-(14)-
hesperetin, naringenin, chlorogenic acid, tannic acid, -l-rhamnopyranosyl(12)--l-arabinopyranosyl]
heterosides (Newby et al., 1980; Volynets et al., 1979; medicagenate,28-O-[-d-xylopyranosyl(14)--l-rham-
Dutu etal., 2002). Phytoestrogens: coumestrol, genistein, nopyranosyl(12)--l-arabinopyranosyl]-3-O--d-
formometin, diadzein, biocanine A (Adler, 1962; Bickhoff glucopyranosylmedicagenate, 28-O-[-d-xylopyranosyl
et al., 1960). Phytosterols: -sitosterol, stigmasterol (1 4)- -l-rhamnopyranosyl(1 2)- -l-
(Timbekova et al., 1996). Polyamines: norspermidine, arabinopyranosyl]-3-O-[-d-glucopyranosyl(12)--d-
norspermine (Rodriguez-Garay et al., 1989). Protein: glucopyranosyl]medicagenate, 28-O-[-d-xylopyranosyl
ferritin, protein phosphatase 2A holoenzyme, -amylase (1 4)- -l-rhamnopyranosyl(1 2)- -l-
(Doehlert et al., 1982; Toth et al., 2000; Barcelo et al., arabinopyranosyl]-3-O--d-glucuronopyranosyl-
1997). Saponins: soyasapogenols, hederagenin, medi- medicagenate, 3-O-[-l-rhamnopyranosyl(12)--d-
cagenic acid (Oleszek & Jurzysta, 1986; Massiot et al., glucopyranosyl(12)--d-glucuropyranosyl]soy-
1988; Oleszek, 1988; Wieslaw et al., 1990), 3-Glc-Glc- asapogenol B (Massiot et al., 1991), dehydrosoyasa-
Rha-28Glc-medicagenic acid, 3-Glc-28-Glc-medicagenic poninI, soyasaponin I, azukisaponin II, azukisaponin V
acid, 3-Glc-malonyl-28-Glc-medicagenic acid, Ara- (Kitagawa etal., 1988). Sterols: -spinasterol, -sitosterol,
Glc-Ara-hederagenin, 3-Glc-Ara-28-Glc hederagenin, stigmasterol, myrsellinol, scopoletin, esculetin (El-Khrisy
hex-hex-bayogenin, 3-Glc-Glc-medicagenic acid, 3-Rha- et al., 1994; Abdel-Hafez, 1993), dihydrospinasterol,
Gal-Glc-soyasapongenol B (soyasapogenol I), 3-Glc- 24-methylcholest-7-enol, stigmasterol, campesterol
Ara-28-Glc-hederagenin, 3-Glc-medicagenic acid,3-Glc- (Li-Shar & Claus, 1988). Thyrotropin-releasing hormone
malonyl-medicageinc acid, Rha-Gal-GlcA soyasapogenol analog (Worthington & Breskin, 1983). Vitamins: A, B1,
E, Rha-hex-hex-soyasapogenol E, Ara-hex-hederagenin, B6, B12, C, D, E, K, niacin, pantothenic acid, biotin, folic
pen-hederagenin (Huhman & Sumner, 2002), zahnic acid (Worthington & Breskin, 1983; Horst et al., 1984).
acids, soyasapogenol A, soyasapogenol B, soyasapogenol Volatile components: terpenes, limonene, linalool, trans-
E, bayogenin glycoside, 3-O-[-d-glucopyranosyl(13)- ocimene, furanoids, nonadienal, 2-methyl 4-pentenai,
-d-glucopyranosyl]-28-O--d-glucopyranoside benzaldehyde, ethyl benzaldehyde, alcohols, butanol,
medicagenate, 3-O-[-l-rhamnopyranosyl(12)--d- hexanol, octanol, pentan-3-ol, 3-methylbutanol, trans-

2011 Informa Healthcare USA, Inc.


214 Kundan Singh Bora, and Anupam Sharma
2-pentenol, trans-2-hexenol, trans-3-hexenol, pent-1- intestinal absorption of cholesterol, increased fecal excre-
en-3-ol, ott-I-en-3-ol, octa-1,5-dien-3-ol, benzyl alcohol, tion of endogenous and exogenous neutral steroids and
2-phenylethanol, ketones, pent-1-en-3-one, pentan-3- bile acids, and decreased the percentage distribution of
one, octan-3-one, methyl phenyl ketone, esters, trans-3- fecal deoxycholic and lithocholic acids (Malinow et al.,
hexenylacetate, trans-3-hexenylbutanoate, aldehydes, 1981a).
hexanal, trans-2-pentenal, trans-2-hexenal, trans-2- Khaleel etal. (2005) performed a study and showed that
nonenal, trans-2,4-hexadienal, furane-2-ethyl (Aldo & highest saponin content extract just before fruiting stage
Luciano, 1997). (free from both coumestrol and canavanine) of M. sativa
Figure 1 shows the chemical structures of common exhibited significant hypocholesterolemic and antiath-
saponin aglycones present in M. sativa. erosclerotic activity. This study proved that M. sativa was
found to safely reduce natural cholesterol and to possess
a strong anti-atherosclerotic activity. The extracts pro-
Pharmacological/clinical reports
duced the most significant decrease in total cholesterol
Several studies indicate that the ingestion of M. sativa and LDL-cholesterol by 85.1 and 88%, respectively, of the
reduces cholesterol absorption and atherosclerotic corresponding levels in hypercholesterolemic rabbits.
plaque formation in animals (Wilcox & Galloway, 1961; This decrease was more significant than that produced
Malinow et al., 1977a, 1981a; Cohen et al., 1990). M. by gemfibrozil (73 and 74%) upon concomitant admin-
sativa top (stem and leaves) saponins have been reported istration with a cholesterol enriched diet using the same
to decrease plasma cholesterol concentrations without animal model at the tested dose level. Moreover, it was
changing high-density lipoprotein cholesterol concen- also observed that all M. sativa preparations produced
trations, decrease intestinal absorption of cholesterol, significant antioxidant properties.
increase excretion of neutral steroids and bile acids, pre- M. sativa when supplied in the diet (6.25% by weight)
vent atherosclerosis and induce the regression of athero- and infusion (1g/400mL) has been reported to reduce
sclerosis (Malinow et al., 1982a). Hypocholesterolemic the level of hyperglycemia in streptozotocin-induced
activity has been reported for root saponins, when given diabetes (Swanston etal., 1990). Aqueous extract of the
to monkeys receiving a high-cholesterol diet (Malinow plant (1mg/mL) stimulated 2-deoxy-glucose transport
etal., 1977b) (1.8-fold), glucose oxidation (1.7-fold) and incorporation
In a study, the ability of M. sativa plant to reduce of glucose into glycogen (1.6-fold) in mouse abdominal
liver cholesterol accumulation in cholesterol-fed rats muscle. In acute, 20min tests, 0.25-1mg/mL aque-
was enhanced by the removal of saponins. Therefore, ous extract of M. sativa evoked a stepwise 2.5-6.3-fold
M. sativa saponins appear to play an important role stimulation of insulin secretion from the BRIN-BD11
in neutral steroid excretion, but are not essential for pancreatic beta cell line. This effect was abolished by
increasing bile acid excretion (Story et al., 1984). In an 0.5mM diazoxide, and prior exposure to the extract did
experiment with prairie dogs, the lowest incidence of not affect subsequent stimulation of insulin secretion by
cholesterol gallstones was served with the diet of the 10mM l-alanine, thereby negating a detrimental effect
higher fiber content (85% alfalfa) (Cohen etal., 1990). on cell viability. The effect of the extract was potenti-
In a short-term study involving three normolipidemic ated by 16.7mM glucose and by 1mM 3-isobutyl-1-
individuals given M. sativa seeds (80-60g daily), serum methylxanthine. l-Alanine (10mM) and a depolarizing
cholesterol concentrations were reported to be reduced. concentration of KCl (25mM) did not increase the insu-
In another small study in which heat-treated M. sativa lin-releasing activity of M. sativa. Sequential extraction
seeds (40g three times daily for eight weeks) were taken with solvents revealed insulin-releasing activity in both
by eight type-IIA hyperlipoproteinemic patients and the methanol and water fractions, indicating a cumula-
three type IIB patients, a significant decrease was noted tive effect of more than one constituent (Mohamed etal.,
in total serum cholesterol concentrations, low-density 2006).
lipoprotein (LDL) cholesterol and apolipoprotein B. The The manganese content of M. sativa (45.5mg/kg)
LDL cholesterol concentration fell by less than 5% in two is reported to be the active principle responsible for a
of the 11 patients (Molgaard et al., 1987). Cholestaid, hypoglycemic effect documented for M. sativa. A diabetic
a product available in the USA containing 900mg of patient, treated with soluble insulin but poorly controlled,
M.sativa extract with 100mg citric acid, is said to neu- found that an M. sativa extract adequately controlled his
tralize the cholesterol in the stomach before it reaches diabetes. When administered separately, only small doses
the liver, thus facilitating the excretion of cholesterol of manganese chloride (5-10mg) were required to have a
from the body with no side effects or toxicity (Levy, 1999; hypoglycemic effect. However, no effect was seen on the
Dewey, 2001). blood sugar concentrations of non-diabetic controls or
M. sativa top saponins have been shown to decrease of other diabetic patients, who were also administered
cholesterolemia without changing the levels of high manganese. It was concluded that manganese lowered
density lipoprotein-cholesterol; hence, they reduced the the blood sugar concentration in this particular diabetic
total cholesterol/high density lipoprotein-cholesterol patient because he was unable to utilize manganese
ratio in Macaca fascicularis. Furthermore, they decreased stored in his body (Rubenstein etal., 1962).

 Pharmaceutical Biology
Medicago sativa: A review 215

OH O CO2H
HO

HO HO HO
CH2OH
CH2OH CO2H

Soyasapogenol B Soyasapogenol E Medicagenic acid

OH
H

OH
HO COOH COOH

HO HO HO
CH2OH CH2OH CH2OH

Bayogenin Hederagenin Soyasapogenol A

OH O

OR2 CO2H
HO

O OH
R 1O R1 = GlcAP Galp Rhap OCH3
CH2OH R2 = H HO
CO2H
Soyasaponin I Formononetin Zahnic acid

Figure 1. Chemical structures of some common saponin aglycones present in M. sativa.

Methanol extract of M. sativa has been shown sig- prolactin, and thyroid stimulating hormone were
nificant estrogenic activity using an estrogen-dependent unchanged. Thus, M. sativa suggested having a cen-
MCF-7 breast cancer cell proliferation assay. The extract tral slight antidopaminergic action without side effects
showed significant competitive binding to estrogen (Minerva, 1998).
receptor (ER). The pure estrogen antagonist, ICI 182,780, Seed extract of M. sativa has been reported to exhibit
suppressed cell proliferation induced by the extract, sug- significant reduction of total cholesterol, phospholipid,
gesting an ER-related signaling pathway was involved. The triglyceride, LDL-cholesterol and VLDL-cholesterol in
ER subtype-selective activities of extract were examined chicks, where clofibrate was used as a standard drug
using transiently transfected human embryonic kidney (Dixit & Joshi, 1985).
(HEK 293) cells. Methanol extract exhibited preferential In an in vitro experiment, polysaccharides isolated
agonist activity toward ER. Phytoestrogens of the extract from M. sativa exhibited immunopotentiating activity by
were determined to be responsible for estrogenic activity increasing mouse lymphocyte uptake of [3H] thymidine
(Boue etal., 2003). (Zhao etal., 1993).
Extract of the leaves from M. sativa has been shown The antimicrobial activity of saponins isolated from
to be used in treatment of neurovegetative menopausal M. sativa against selected medically important yeasts,
symptoms in women. Hot flushes and night sweating Gram-positive and -negative bacteria has been investi-
completely disappeared with the treatment of M.sativa gated. Increasing antibiotic activity was observed going
extract. The plant product induced a significant increase from the saponin extracts to the sapogenin samples,
in prolactin and thyroid stimulating hormone response suggesting that the sugar moiety is not important for
to thyroid releasing hormone. Basal levels of estradiol, the antimicrobial efficacy. Activity was found especially
luteinizing hormone, follicle stimulating hormone, high against Gram-positive bacteria (Bacillus cereus,
2011 Informa Healthcare USA, Inc.
216 Kundan Singh Bora, and Anupam Sharma
B. subtilis, Staphylococcus aureus, and Enterococcus Recently, the authors have shown that M. sativa exhib-
faecalis). Discrete antifungal activity was also observed, ited significant antioxidant and cerebroprotective effects
mainly against Saccharomyces cerevisiae. The observed against ischemia and reperfusion insult in mice (Kundan
antimicrobial properties of M. sativa were related to the & Anupam, 2010). Pretreatment with M. sativa extract
content of medicagenic acid (Avato etal., 2006). (100 or 200mg kg1, p.o.) markedly reduced cerebral
An investigation into the effect of various herbs on infarct size, xanthine oxidase, superoxide anion and thio-
hepatic drug metabolizing enzymes in the rat, showed barbituric acid-reactive substance levels, significantly
that M. sativa potentiated the activity of aminopy- restored reduced glutathione, superoxide dismutase and
rine N-demethylase but had no effect on glutathione total tissue sulfhydryl levels and attenuated impairment
S-transferase or epoxide hydrolase activities (Garrett in short-term memory and motor coordination. In addi-
etal., 1982). tion, M. sativa directly scavenged free radicals generated
M. sativa can be used as an alternative natural carote- against a stable radical 1,1-diphenyl-2-picrylhydrazyl
noid instead of the synthetic apo-ester in goldfish diets and, superoxide anion radicals generated in phenazine
(Yanar etal., 2008). methosulfate-nicotinamide adenine dinucleotide sys-
Medicagenic acid isolated from M. sativa exhibited tems, and also inhibited xanthine dehydrogenase/xan-
significant nematicidal activity against the plant-parasitic thine oxidase conversion and resultant superoxide anion
nematode Xiphinema index (Argentieri etal., 2008). production.
Refined components of M. sativa polysaccharides In addition to the above mentioned activities, M. sativa
have been shown to inhibit the activities of reverse is also considered beneficial in arthritis (Hall, 1981), car-
transcriptase of HIV and protease of HIV (Zhang et al., diovascular complaints (Reilly, 1989), convalescence,
2006). debility (Mills, 1994) and dysuria (Duke, 2002). The plant
Health beverage manufactured from M. sativa buds is said to promote weight gain (Meyer, 1954), and can be
was found beneficial in maintaining normal digestive useful for people with protein allergies (Hall, 1981), GI
function and nutrition balance in human body, reducing cramping and colic (Reilly, 1989), gravel (Duke, 2002),
cholesterol, and preventing osteoporosis, arteriosclerosis hyperacidic stomach (Hall, 1981), hypoestrogenism/
and aging (Song & Wei, 2007). hyperestrogenism (Reilly, 1989). It also improves appe-
The saponin extract of M. sativa containing hederagen- tite (Lust, 1974), and intellect (Duke, 2002). l-Canaverine
ins and saponin compounds I, II and III was reported to isolated from the plant has been shown to have antitu-
be used in manufacturing of hypolipidemic agents and mor activity against certain types of leukemia cells in
antiatherosclerotics (Yu etal., 2007). mice and selective toxicity in dog cancer cells grown
The dried powder of M. sativa has been shown to invitro (Hendler, 1995). M. sativa has been reported to be
inhibit the germination and growth of Echinochloa beneficial in the treatment of peptic ulcers (Lust, 1974),
crus-galli Wight (Gwon & Kim, 2006). polycystic ovaries (Reilly, 1989), prolactin excess (Reilly,
Xiong (2003) demonstrated that extracts prepared 1989), hemorrhage, as a tonic after blood loss and during
from M. sativa roots may be used to prepare medical anemia (Mills, 1994), urinary and bowel problems (Lust,
preparations like powder, pill, or decoction for lowering 1974), scurvy (Duke, 2002), secondary hypothyroidism
the levels of cholesterol and lipid in blood, improving the (Reilly, 1989) and Herpes simplex (Hendler, 1995).
liver function and the control and transmission of nerve
tissue, and treating calculus.
Toxicity/side-effects
Among M. sativa secondary metabolites, saponins and
phytoestrogens offer interesting medicinal and nutraceu- Both M. sativa seed and herb have been reported to
tical prospects. Phytoestrogens, mainly coumestrol, api- induce a systemic lupus erythematosus (SLE)-like syn-
genin and quercetin exhibit strong estrogenic activity and drome in female monkeys (Barnes et al. 2007; Boon &
have potential for use in treatment of hormone-related Smith, 2004; Brinker, 2001; Malinow etal., 1982a, 1982b).
cancers (Huyghe etal., 2007). This activity has been attributed to canavanine, a non-
The extracts prepared from M. sativa flowery aerial protein amino acid constituent, which has been found
parts and seeds exhibited significant in vitro and in vivo to have effects on human immunoregulatory cells in
antimitotic activities (Dutu etal., 2002). vitro (Jorge etal., 1985). Re-activation of quiescent SLE
Saponins isolated from the aerial parts of M. sativa in humans has been associated with the ingestion of M.
have been shown to stimulate lipolytic activity without sativa tablets which, following analysis, were found to
influencing amylolytic or proteolytic activity of Neo- contain canavanine (Roberts & Hayashi, 1983). It was
Pancreatinum (Sroka etal., 1997). not stated whether the tablets contained seed or herb
Triterpenoid glycosides of the roots and leaves of material. Canavanine is known to be toxic to all animal
M. sativa have shown antibacterial activity against species because it is a structural analogue of arginine
Corynebacterium michiganense, Corynebacterium insi- and may interfere with the binding of this amino acid to
diosum, and Agrobacterium tumefaciens. The inhibitory enzymes and its incorporation into proteins. M. sativa
effects of these glycosides on cotton and cabbage seed seeds are reported to contain substantial quantities of
germinations have also been tested (Timbekova, 1995). canavanine (8.33-13.6mg/kg), whereas the herb is stated

 Pharmaceutical Biology
Medicago sativa: A review 217
to contain amounts that are considerably less (Natelson, immense potential of medicinal plants used in various
1985). traditional systems. The present review emphasizes the
Pancytopenia has been associated with human inges- phytochemical, traditional, pharmacological, clinical
tion of ground M. sativa seeds (80-160g/day), which and toxicological reports on M. sativa. Saponins, fla-
were taken to lower plasma cholesterol concentrations vonoids, phytoestrogens, coumarins, alkaloids, amino
(Malinow etal., 1981a). Dietary studies using alfalfa top acids, phytosterols, vitamins, digestive enzymes and
saponins (ATS) in the diet of rats and monkeys showed terpenes constitute major classes of phytoconstituents
no evidence of toxicity and serum lipid concentrations of the plant. M. sativa has been used since centuries as
were lowered (Malinow etal., 1982a, 1981a). In addition, homoeopathic and Ayurvedic medicine for a variety of
when ATS were given to cholesterol-fed animals, a reduc- ailments. The plant is widely used in foods and is listed
tion in serum lipid concentrations was observed. ATS are by the Council of Europe as a source of natural food fla-
reported to be free of the SLE-inducing substance that vor (category N2 and N3). These categories indicate that
is present in the seeds (Malinow etal., 1982c). Negative M.sativa can be added to foodstuffs in small quantities
results were documented for M. sativa when tested for with a limitation on the concentrations of an active
mutagenicity using Salmonella strains TA98 and TA100 ingredient in the final product. In the USA, M. sativa is
(White etal., 1983). listed as GRAS (generally recognized as safe). Recent
Consultation is a necessity for a health care practi- research carried out indicates its uses such as neuro-
tioner prior to prescribe use of M. sativa if undergoing protective, hypocholesterolemic, antioxidant, antiulcer,
hormone replacement therapy or taking birth control antimicrobial, hypolipidemic, immunopotentiating,
medication or using blood thinners (Barnes etal. 2007; estrogenic, digestive, nutritive for human body, and in
Boon & Smith, 2004; Brinker, 2001). the treatment of atherosclerosis, heart disease, stroke,
cancer, diabetes and neurovegetative menopausal
Doses symptoms in women.
Preparations equivalent to 930g dried aerial parts, The presence of a wide range of chemical com-
per day (Mills, 1985; BHMA, 1983) pounds indicates that the plant could lead the way for
Dried aerial parts: 510g, 3 times per day (BHMA, the development of novel agents having good biologi-
1983). 310g, 3 times per day (Mills, 1985) cal activity. Exploration of the chemical compounds
Infusion: 510g dried aerial parts, 3 times per day of the plant will provide the basis for developing such
(BHMA, 1983) a lead. Many chemical compounds are present in the
Fluid extract: 510g dried equivalent, 3 times per day plant but isolation of active constituents by using vari-
(BHMA, 1983) (1:1, 25% alcohol, 510mL) ous appropriate chromatographic techniques should
Tablets: A dose of two tablets (1g each) of Cholestaid be carried out. Further studies can be carried out
(esterin processed M. sativa) taken by mouth 3 times using different extraction methods such as microwave
daily for up to two months, then one tablet 3 times extraction, isolation and identification of active com-
daily, has been recommended (Farnsworth, 1995). pounds, pharmacological screening of extracts as well
Seeds: For treating high cholesterol, a dose of 40g of as isolated compound(s) so that accuracy of results can
heated seeds taken by mouth 3 times daily has been be obtained and use of extracts can be made in differ-
recommended (Farnsworth, 1995). ent herbal formulation. Despite a long tradition of use
of M. sativa for treatment of various ailments, only spo-
Contraindications radic pharmacological work has so far been carried out
People with a history of lupus or a family history of to prove its traditional claims. Additionally, the plant
systemic lupus erythematosus should avoid M. sativa has been included in a number of herbal and homoeo-
supplements (Barnes etal. 2007; Boon & Smith, 2004; pathic formulations, which are in clinical use for the
Brinker, 2001). treatment of various ailments. M. sativa seems to hold
M. sativa seeds should not be ingested during preg- great potential for in depth investigation for various
nancy or lactation (Brinker, 2001). biological activities. Therefore, it is necessary to exploit
its maximum potential in the field of medicinal and
pharmaceutical sciences for novel and fruitful applica-
Discussion
tion Currently, the authors are involved in evaluating
Plants have played a significant role in maintaining the CNS effects of traditionally used medicinal plants,
human health and improving the quality of human life including M. sativa, with a view to isolating bioactive
for thousands of years, and have served humans well as phytoconstituent(s).
valuable components of medicines, seasonings, bev-
erages, cosmetics and dyes. Herbal medicine is based
Declaration of interest
on the premise that plants contain natural substances
that can promote health and alleviate illness. In recent Financial support from the L.L.R. Educational Trust,
times, focus on plant research has increased all over the Solan, Himachal Pradesh, India, which runs the
world and a large body of evidence has collected to show L.R. Institute of Pharmacy, is gratefully acknowledged.

2011 Informa Healthcare USA, Inc.


218 Kundan Singh Bora, and Anupam Sharma
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