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Efficacy and safety of Stephania glabra: An alkaloid-rich traditional medicinal

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Efficacy and safety of Stephania glabra:

an alkaloid-rich traditional medicinal
plant
ab ab
Deepak Kumar Semwal & Ruchi Badoni Semwal
a
Department of Chemistry, Panjab University, Chandigarh160014,
India
b
Department of Pharmaceutical Sciences, Tshwane University of
Technology, Pretoria0001, South Africa
Published online: 04 Sep 2014.
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To cite this article: Deepak Kumar Semwal & Ruchi Badoni Semwal (2015) Efficacy and safety of
Stephania glabra: an alkaloid-rich traditional medicinal plant, Natural Product Research: Formerly
Natural Product Letters, 29:5, 396-410, DOI: 10.1080/14786419.2014.955487

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 Natural Product Research, 2015
Vol. 29, No. 5, 396–410, http://dx.doi.org/10.1080/14786419.2014.955487

REVIEW
Efficacy and safety of Stephania glabra: an alkaloid-rich traditional
medicinal plant
Deepak Kumar Semwalab* and Ruchi Badoni Semwalab*
a
Department of Chemistry, Panjab University, Chandigarh 160014, India; bDepartment of Pharmaceutical
Sciences, Tshwane University of Technology, Pretoria 0001, South Africa
Downloaded by [Tshwane University of Technology] at 22:19 11 January 2015

(Received 23 June 2014; final version received 11 August 2014)

Stephania glabra (Roxb.) Miers (Menispermaceae) has long been used for the
treatment of asthma, tuberculosis, dysentery, hyperglycaemia, cancer, fever, intestinal
complaints, sleep disturbances and inflammation in many Asian countries. It mainly
contains alkaloids and, until now, over 30 alkaloids such as bisbenzylisoquinolines,
hasubanalactams, berberines and aporphines have been isolated from its tuber. Most of
its traditional medicinal activities are scientifically approved by various in vitro and
in vivo studies. It shows remarkable anti-psychotic, anti-diabetic, antipyretic, analgesic,
antimicrobial and anti-hypertensive activities. This work includes comprehensive
information on the ethnobotany, chemistry and pharmacology of S. glabra. This review
also focuses on the future perspectives with main emphasis on the establishment of
therapeutic index and safety index of the plant. This review concludes that S. glabra has
a great potential to treat various diseases, and could be used as a source for novel
healthcare products in the near future, which needs further studies.
Keywords: anti-hyperglycaemic activity; anti-psychotic activity; bisbenzylisoquino-
lines; cycleanine; pronuciferine; Stephania glabra

1. Introduction
The genus Stephania belongs to Menispermaceae family, a large family which comprises around
65 genera and 350 species, growing in warmer regions of the globe. These plants are mostly
climbing shrubs with peltate and membranous leaves (Semwal, Badoni, Semwal, et al. 2010;
Semwal et al. 2014). Stephania is the largest genus of the family Menispermaceae which
comprises 43 species followed by Odontocarya (37), Cyclea (36), Abuta (33), Disciphania (26),
Tiliacora (24) and Cissampelos (21) (The Plant List, 2013). In traditional medicine, most of the
plants of this genus are used to treat a variety of ailments such as diarrhoea, pyrexia,
tuberculosis, dyspepsia, urinary troubles, abdominal ills, asthma, ascariasis (a disease caused by
the parasitic roundworm Ascaris lumbricoides), dysmenorrhoea, wounds, head-ache, sore-
breasts and leprosy. Stephania glabra (Roxb.) Miers, vern. Gindaru is one of the well-known
members of this genus. It is a large, climbing shrub, indigenous to the lower parts of Indian
Himalayan region. The plant usually grows in tropical and temperate regions of Himalaya,
expanding to an altitude of 2200 m from Sindh eastwards to Khasia hills and Pegu (Gaur 1999).
This plant mainly grows in the tropical regions of India, Burma and China. It is also found in
Adzharia, coast of the Black Sea in Russia (Titova et al. 2012).
Previously, this plant was known as Cissampelos glabra (Roxburgh 1832) due to its similar
taxonomical characteristics with the genus Cissampelos, and later it was shifted to the genus

*Corresponding authors. Email: dr_dks.1983@yahoo.co.in; ruchi_badoni26@yahoo.com

q 2014 Taylor & Francis

 Natural Product Research 397
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Figure 1. Flowering twig, fruits and tuber of S. glabra.

Stephania on the basis of different floral description than Cissampelos. Moreover, in few reports,
it was also named as Stephania rotunda Lour. (Kin et al. 1965). The plant has herbaceous vines,
and striate, glabrous and hollow stems. The petioles are thin up to 15 cm in length, geniculate
and somewhat thicker at the base. The leaves are narrow peltate, broad ovate, papery or
membranous, glabrous with five palmately veins, and round base. The inflorescences are
filamentous, axillary or found on leafless old stems with 4– 8 cm peduncle and six umbellet rays.
The flowers comprise six sepals, three petals and 1 –2 mm synandrium. The fruits are pedicels
while drupes are obovate and flattened. The roots are tuberous, perennial and usually irregular
roundish in shape (Figure 1) (Roxburgh 1832; Gaur 1999).
S. glabra is regarded as an endangered plant in some parts of its range in India because of its
overuse in traditional medicine (Chhetri, Basnet, et al. 2005). Phytochemical studies on the plant
led to the isolation of over 30 alkaloids together with a very few flavonoids, and other
constituents (Bhakuni & Gupta 1982; Pal et al. 1995). However, only a few of them have been
studied for their pharmacological efficacy. Herein, we discuss the ethnobotany, phytochemistry
and pharmacology of S. glabra which included our previous research on its tubers.

2. Taxonomical classification

Kingdom : Plantae
Division : Magnoliophyta
Class : Magnoliopsida
Order : Ranunculales
Family : Menispermaceae
Genus : Stephania
Species : glabra

3. Ethnobotanical relevance
S. glabra is a well recognised plant in Indian Ayurveda and Chinese traditional medicine for the
treatment of various human ailments. The tuber is an ethnobotanically most important part that is
 398 D.K. Semwal and R.B. Semwal

used to treat asthma, diabetes, cancer, intestinal troubles, tuberculosis, dysentery, sleep
disturbances, psycho-disorders, inflammation and fever in many Asian countries (Gaur 1999;
Semwal, Badoni, Semwal, et al. 2010). Aqueous extract of the tubers is used for treatment of
various types of fevers such as common fever, filariasis (a parasitic disease caused by filarial
worms), malaria, pneumonia and typhoid in various parts of India (Singh & Ali 1994).
Decoction of the tubers has long been used as an anti-dysenteric, antipyretic, anti-asthmatic,
anti-tubercular and anti-diabetic agent in India (Chopra et al. 1958; Kirtikar & Basu 2004;
Semwal et al. 2007). It is also used as an anti-diabetic remedy by various tribes of north-eastern
India (Chhetri, Parajuli, et al. 2005). An aqueous mixture of the powders of dried rhizomes of
S. glabra and aerial roots of Trichosanthes multiloba Miq. (Cucurbitaceae) is used as an
anthelmintic against intestinal worms in north-east India (Das et al. 2004). Various parts of the
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plant are also used to treat diabetes, oedema, pain, stomach disorders, helminthiasis, malaria,
hepatitis, tuberculosis and hypertension in Bangladesh (Jahan et al. 2010). A dried powder of the
root pulp with tea is used to treat puerperal fever in women in some parts of Bangladesh
(Rahmatullah et al. 2014).
Apart from its traditional medicinal uses for human beings, it is also used to treat various
ailments of livestock such as buffalo, cow, oxen, sheep, goat, horse, mule, dog and cat, and is
considered to be a veterinary medicine in various parts of northern India (Singh 1995; Phondani
et al. 2010).

4. Phytochemical studies
The available literature as well as our own studies on S. glabra revealed that it usually contains
alkaloids together with other constituents in lesser amount. The earlier phytochemical studies
including our own research found only non-volatiles in the tubers, but a peculiar report by
Hemraj et al. (2012) advocated the presence of essential oil in dry powder of the tubers. This was
a preliminary isolation-based study which did not report the identification of essential oil. If the
tubers contain essential oil, its composition is to be identified which requires a further study.
The first phytochemical report on the plant is documented in 1950, which conferred the
isolation of three crystalline alkaloids named gindarine (1), gindaricine (2) and gindarinine (3)
from the tubers, among them 1 is also found in the form of its nitrate base (Chaudhary & Siddiqui
1950). A following study by Chaudhary et al. (1952) found that the structures of 1 and 3 are
identical to that of tetrahydropalmatine (syn. rotundine, hyndarine) (1) and palmatine (3),
respectively. After 16 years, Cava et al. (1968) suggested that the structure of gindaricine is most
likely similar to that of stepharine due to similarity in their analytical values. Hence, we are
providing the same structure, i.e. 2 for both gindaricine and stepharine as no further report is
available about this alkaloid. Shchelchkova et al. (1965) isolated stepharine (2) and cycleanine
(4) together with 1 and an unidentified alkaloid having molecular formula C19H21O4N. A further
study by same research group (Kin et al., 1965) found three new unidentified alkaloids with
molecular formulae C19H18O2N, C20H25O4N and C21H25O4N. Afterward, Wa et al. (1967)
isolated 3, columbamine (5), jatrorrhizine (6) and magnoflorine (7) from the tubers. They
crystallised 3 as chloride and iodide, 5 and 6 as iodide and 7 as styphnate. In the same year, this
group identified stepharanine (8) and dehydrocorydalmine (9) from the same source (Doskotch
et al. 1967). In the following year, Cava et al. (1968) separated 1, 2, pronuciferine (10),
corydalmine (11) and stepholidine (12). Thu and Nuhn (1971) reported roemerine (13) from the
tubers of S. glabra. Wahi et al. (1977) further isolated 1 and its tautomer from the tubers together
with one unidentified alkaloid having melting point of 1808C. Furthermore, from the same
source, Patra et al. (1980) separated palmatrubine (14) together with 1, 3, 8, 9, 11 and 12.
Bhakuni and Gupta (1982) reported N-desmethylcycleanine (15), capaurine (16) and
corynoxidine (17) along with 1 –4, 6, 8 – 12 from the rhizomes. This study suggested that the
 Natural Product Research 399

concentration of all these alkaloids is similar to that in rhizomes, leaves and stems of the plant.
Interestingly, there was no phytochemical work manifested between 1982 and 2005. Afterward,
a non-alkaloid, isoflavonoid C-glycoside named 40 ,5,7-trihydroxy-8-C-glucosylisoflavone (18),
has been reported from this source for the first time (Pal et al. 1995; Reynaud et al. 2005).
Thereafter, our research on the tubers of this plant yielded glabradine or 7-O-demethyl-N,O-
dimethyloxostephinine (19) (Semwal & Rawat 2009a), gindarudine or 3,6-O,N-detrimethyl-10-
hydroxy-1-methoxy-thebaine (20) (Semwal & Rawat, 2009b), 11-hydroxypalmatine (21)
(Semwal, Rawat, Semwal, et al. 2010) and 8-(40 -methoxybenzyl)-xylopinine (22) (Semwal et al.
2012), accompanied by 3, 8 and 9. In addition of the above phytochemicals, few more alkaloids
such as stephararine, N-methyloxystephanine, N-methylhydoxystepharine (Duke 2000),
cepharamine (23) and tuduranine (24) (Rastogi & Mehrotra 1991a, 1991c) also appeared in
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the literature. However, we could not find the original database of these alkaloids.
Apart from the above phytochemicals, the tubers of the plant also contain starch with
spherical or polygonal shape, and having good water binding capacity. The isolated starch was
found to have protein, phosphorus, fat and amylose (Soni et al. 1986). Chemical constituents
isolated from the tubers of S. glabra are shown in Table 1, and their structures are depicted in
Figure 2.

5. Biosynthesis of alkaloids in S. glabra

A biosynthesis-based study by Bhakuni et al. (1983) revealed that the tetrahydroprotoberberine
alkaloids (11, 12, 16 and 17) are biosynthesised from (S)-reticuline (25) while the
bisbenzylisoquinoline alkaloids (4 and 15) and the proaporphine alkaloids (2 and 10) are
biosynthesised from (R)-N-methylcoclaurine (26) in young plants. However, the quaternary
protoberberine alkaloids are formed by dehydrogenation of their corresponding tetrahydropro-
toberberines. In addition, Bhakuni and coworkers (Bhakuni et al. 1980; Bhakuni 2002) also
established the biosynthetic pathway of 7 as tyrosine (27) ! norlaudanosoline (28) ! (þ )-(S)-
reticuline ! magnoflorine (7). The precursors which involve in these processes are depicted in
Figure 3. A study by Titova et al. (2011) revealed that breathing or respiration activity of
suspension culture of cells of S. glabra (contains 2) can be used to observe the growth and
biosynthesis of alkaloids in producing cell cultures during deep cultivation. The study suggested
that peculiarities of breathing of cultures of cells produce bioactive alkaloids. The study also

Table 1. Chemical constituents isolated from the tubers of S. glabra.

Isolated compounds Reference

Tetrahydropalmatine (1); gindaricine (2); palmatine (3) Chaudhary & Siddiqui (1950)
Cycleanine (4) Shchelchkova et al. (1965)
Columbamine (5); jatrorrhizine (6); magnoflorine (7) Wa et al. (1967)
Stepharanine (8); dehydrocorydalmine (9) Doskotch et al. (1967)
Pronuciferine (10); corydalmine (11); stepholidine (12) Cava et al. (1968)
Roemerine (13) Thu & Nuhn (1971)
Palmatrubine (14) Patra et al. (1980)
N-desmethylcycleanine (15); capaurine (16); corynoxidine (17) Bhakuni & Gupta (1982)
40 ,5,7-Trihydroxy-8-C-glucosylisoflavone (18) Pal et al. (1995)
Glabradine (19) Semwal & Rawat (2009a)
Gindarudine (20) Semwal & Rawat (2009b)
11-Hydroxypalmatine (21) Semwal, Rawat, Semwal, et al. (2010)
8-(40 -Methoxybenzyl)-xylopinine (22) Semwal et al. (2012)
Cepharamine (23); tuduranine (24) Rastogi & Mehrotra (1991a, 1991c)
 400 D.K. Semwal and R.B. Semwal

R3
H3CO H3CO

N
R2 N
H3CO R
H H
R1 R4

R5 O

R6
Tetrahydropalmatine [R1=H, R2=OCH3, R3=H, R4=OCH3, R5=OCH3, R6=H] (1)
Corydalmine [R1=H, R2=OCH3, R3=H, R4=OCH3, R5=OH, R6=H] (11) Stepharine [R=H] (2)
Stepholidine [R1=H, R2=OH, R3=H, R4=OCH3, R5=OH, R6=H] (12) Pronuciferine [R=CH3] (10)
Capaurine [R1=OH, R2=OCH3, R3=H, R4=OCH3, R5=OH, R6=H] (16)
H3CO
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R1O N
H3CO R
+ - O H
N X
R2O
OR5

X=Cl, I or NO3
OR4 H O
OCH3
R3 N

OCH3
Palmatine [R1=CH3, R2=CH3, R3=H, R4=CH3, R5=CH3] (3)
Columbamine [R1=CH3, R2=H, R3=H, R4=CH3, R5=CH3] (5)
Jatrorrhizine [R1=H, R2=CH3, R3=H, R4=CH3, R5=CH3] (6)
Cycleanine [R=CH3] (4)
Stepharanine [R1=CH3, R2=H, R3=H, R4=H, R5=CH3] (8)
N-Desmethylcycleanine [R=H] (15)
Dehydrocorydalmine [R1=CH3, R2=CH3, R3=H, R4=H, R5=CH3] (9)
Palmatrubine [R1=CH3, R2=CH3, R3=H, R4=CH3, R5=H] (14)
11-Hydroxypalmatine [R1=CH3, R2=CH3, R3=OCH3, R4=CH3, R5=CH3] (21)

H3CO O H3CO
O O
+
N N
HO H3CO
H
HO OCH3

N
H3CO OCH3
Magnoflorine (7) Roemerine (13) Corynoxidine (17)

OH
O
H OH
H O HO OCH3
OH H
HO
O OH
H OH O
O
HO O
N NH
O

HO OCH3 HO
OH O OH
OH
4’5,7-Trihydroxy-8-C-glucosylisoflavone (18) Glabradine (19) Gindarudine (20)

H3CO H3CO
OCH3
N H3CO
H3CO HO
HO
OCH3 N

OCH3 N
O H
OCH3 OCH3
8-(4’-methoxybenzyl) xylopinine (22) Cepharamine (23) Tuduranine (24)

Figure 2. Chemical structures of constituents isolated from S. glabra.

 Natural Product Research 401

H3CO H3CO

N N
HO HO

OH

OCH3 OH
(S)-Reticuline (25) (R)-N-Methylcoclaurine (26)

HO

O
NH
HO
OH
OH
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NH2
HO

OH
Tyrosine (27) Norlaudanosoline (28)

Figure 3. Precursors involved in the biosynthesis of alkaloids in S. glabra.

showed that highest oxygen consumption rate for cells occurs in the period preceding active
synthesis of alkaloids.

6. Pharmacological studies
S. glabra possesses a variety of pharmacological activities in both in vitro and in vivo models.
The potential anti-inflammatory, analgesic, antipsychotic, anti-diabetic and many other
activities of S. glabra are evidenced from its previous database (Kaz’mina & Rabinovich
1968; Salo & Rabinovich 1970; Khanna et al. 1972; Madan et al. 1974). Many of its alkaloids
have also been used as adenylate cyclase and nitric oxide (NO) activators, which might be
helpful in treating obesity and atherosclerosis (Veeresham 2012). The plant tubers are
traditionally used in tuberculosis, but our preliminary study based on the in vitro anti-
tuberculosis screening of ethanol extract of the tubers shows no activity against
Mycobacterium tuberculosis even with highest dose of 100 mg/mL (Semwal DK, unreported
data). This study reveals that either the plant tuber does not have anti-tubercular potential or a
high dose is required for this effect, which might be toxic, and special concern is needed for
its use. Many studies on various crude extracts as well as the purified alkaloids obtained from
S. glabra showed the following activities, among them, most of the studies are preliminary.
Hence, further in vivo studies, including mechanism of action, are needed to validate its use as
medicine.

6.1. Central nervous system-related activities

6.1.1. Anti-anxiety and neuro-protective activities
Gindarine (1), a natural tranquilliser, could relieve anxiety by inducing sleep at a desired dose.
Its intragastric administration to rats, at the doses less than 50 mg/kg body weight, shows anti-
anxiety activity without producing any toxic effects (Arzamastsev et al. 1983). Tetrahy-
dropalmatine (1), derived from the tubers of S. glabra, produces remarkable sedation of the
central nervous system (CNS), and also exerts significant effects against dopamine receptors
localised in the brain. It antagonises the acetylcholine-, serotonin-, histamine- and bradykinin-
induced contractions in the isolated guinea pig ileum. Compound 1 inhibits contraction in a non-
specific similar way to papaverine, although 1 is less active than papaverine and chlorpromazine.
The mean effective concentration of 1 was found to be 4.4 £ 105 – 7.3 £ 105 M/L against all
 402 D.K. Semwal and R.B. Semwal

tested agonists in 60 min (Rojas et al. 2006). Hsieh et al. (1994) found that 1 reduces the motor
activity and the brain monoamine concentration in rats. It increases the effect of haloperidol, and
reduces the apomorphine-induced hyper-motility. However, rigidity was noticed at a higher
dosage in rats. Both low and high doses of 1 reduced the concentration of norepinephrine and
dopamine in the cortex and brain stem, whereas only high dose was found capable to decrease
serotonin concentration in the cortex. Lin and coworkers (Chang & Lin 2001; Lin et al. 2002)
found that 1 blocks the picrotoxin-induced motor effects and convulsions, and also protects from
the development of amygdala kindling seizures with amygdaloid dopamine release up to
2 20 nM in rats under general anaesthesia at intraperitoneal doses of 10 and 15 mg/kg body
weight. From the study, it could be suggested that 1 acts through inhibition of amygdaloid
dopamine release to inhibit an epileptic attack. Rotundine (1) exerts promising neuro-sedative
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activity similar to that of chlorpromazine in rats and mice. The levo/(2 ) isomer of 1 shows
higher activity than dextro/(þ ) isomer, and produces less toxic effects by 33 – 50% in
comparison with positive control chlorpromazine (Rastogi & Mehrotra 1991a). Gindarinine (3),
in the form of hydrochloride purified from the tubers, has been found to possess local anaesthetic
effects (Mahatma et al. 1987). Gindarine (1) as hydrochloride reduces the spontaneous motor
activity in rats and mice without producing weakness to the muscles. In rats, 1 causes
hyperthermia, while in mice, it extends pentobarbital-induced hypnosis, a psychological state
resembling to sleep but unconnected to a conscious state (Rastogi & Mehrotra 1991b). However,
the detailed database about these studies, i.e. the doses form, type of study and duration of the
treatment, is not accessible.

6.1.2. Acetylcholinesterase inhibitory activity

Acetylcholinesterase (AChE), an enzyme that hydrolyses the neurotransmitter acetylcholine
(Figure 4), is found in neuro-muscular joints and cholinergic brain synapses, and is responsible
for the termination of synaptic transmission resulting in the loss of cognitive ability, a primary
stage of Alzheimer’s disease (Quinn 1987). Stepharanine (8), a quaternary protoberberine
alkaloid, exerts inhibitory activity against AChE with an IC50 value of 14.10 mM. To determine
the structure – activity relationship, the activity of 8 was compared with structurally related
alkaloids palmatine (3) and jatrorrhizine (6), and also with tertiary protoberberine alkaloids,
corydalmine (11) and stepholidine (12). The study revealed that the positive charge and steric
substitution at nitrogen as well as planarity of the structure or substitutions at C-2, -3, -9 and -10
are perhaps responsible for the anti-AChE activity of protoberberine alkaloids (Ingkaninan et al.
2006). An in vitro study revealed that stepharine (2) inhibits cholinesterase and pseudo-
cholinesterase enzymes. Moreover, 2 enhances the sensitivity of isolated frog abdominal muscle
and rabbit intestine to acetylcholine (Rastogi & Mehrotra 1991b). The doses form of 2 in the
experiment is not clearly mentioned, hence, it needs further studies before opting for clinical
trials. Stephaglabrini sulfas, a drug manufactured from stepharine (2), is an efficient drug used to
decrease trophic disorders of denervated extremities. It also enhanced the earlier and more
complete regeneration of injured nerves, and exhibited a potent anti-AChE activity (Sokolov &
Zamotaev 1990).

O O–
+ AChE [enzyme] +
N N O
O [H2O] HO
Acetylcholine

Figure 4. Hydrolysis of acetylcholine.

 Natural Product Research 403

6.2. Anti-hypertensive activity

Intravenous administration of L -stepholidine (12) with the doses of 0.5 and 2.5 mg/kg body
weight decreases the blood pressure by 29% and 30% in anaesthetised rats and dogs,
respectively. However, 12 raises the blood pressure in reserpinised rats and dogs with the same
doses. Furthermore, 12 inhibits the pressure response to noradrenaline or clonidine, and reverses
the pressure response induced by adrenaline, and also blocks postsynaptic a-adrenoceptors with
a dose of 5.50 mg/kg, when administered intravenously. Phenoxybenzamine (2.5 mg/kg) and
prazosin (1 mg/kg) were used as positive controls in the study (Xiong et al. 1987).
Tetrahydropalmatine (1) shows anti-hypertension activity via inhibition of dopamine-D2
receptors in CNS, resulting in the arterial hypotension and bradycardia in rats. Intravenous
administration of 1 exhibited hypotension and bradycardia, and also increased dopamine release
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in the striatum in rats at the doses of , 10 mg/kg, body weight. The hypotension induced by 1
was attenuated by pretreatment with spinal transection or amphetamine, whereas bradycardia
was attenuated by bilateral vagotomy or amphetamine (Chueh et al. 1995; Lin et al. 1996).
Cycleanine (4), a bisbenzylisoquinoline alkaloid, shows anti-hypertension effects on cardiac and
smooth muscle preparations in in vivo models, and could be used as an effective vascular
selective Ca-antagonist. It exerts inhibitory activity against the KCl-induced contraction of
rabbit aortic rings with an IC50 value of 0.8 M, this activity was found superior than that of
standard nifedipine (IC50 ¼ 7 nM). However, it shows comparatively weaker activity against the
norepinephrine-induced contraction of rabbit aortic rings. Moreover, 4 has also been found to
depress the contraction of rat ventricular preparations, decrease action potential duration of right
ventricular strips and inhibit L-type Ca-current of single rat ventricular cardiomyocytes with an
IC50 value of 3 M. However, the activity was considered to be mild when compared with
nifedipine (IC50 ¼ 0.03 mM) (Martı́nez et al. 1998). An in vivo study suggested that gindarine
(1) reduces arterial blood pressure, heart rate, cardiac contractility and skeletal muscles.
Moreover, an intravenous administration of 10 mg/kg body weight of 1 in the form of
hydrochloride decreases the fibrillation time in acetylcholine-induced fibrillation by 7.5% in dog
(Rastogi & Mehrotra 1991b).

6.3. Muscle-relaxant activity

Pronuciferine (10), as hydrochloride, exhibits spasmolytic activity by reducing the level of
muscle contractions. A blockage up to 75% in the tissue ileum of a guinea pig was noticed at a
dose of 25 mg/mL (Bhakuni & Gupta 1982). A total alkaloid fraction from the tubers of the plant
was found to reduce the amplitude and frequency of natural contraction of intestine and uterus in
rats with the concentration ranging from 1 to 10 mg/mL. The fraction also decreases
acetylcholine-, serotonin-, histamine- and barium chloride-induced contractions in the smooth
muscle of intestine and uterus (Rastogi & Mehrotra 1991d).

6.4. Antimicrobial activity

An ethanolic extract of the tubers shows broad spectrum antimicrobial activity against five
bacterial species (Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus mutans,
Escherichia coli and Klebsiella pneumonia) and six fungal species (Aspergillus niger,
Aspergillus fumigatus, Penicillum citranum, Microsporum gypseum, Microsporum canis and
Trichophyton rubrum), with IZD values ranging from 6 to 28 mm against bacterial and from
15 to 35 mm against fungal pathogens at a concentration of 100 mg/mL in each case. The MIC
values were found ranging from 25 to 100 mg/mL against all test strains. The standard drugs
novobiocin (against bacterial species) and erythromycin (against fungal species) show IZD
values ranging from 12 to 25 mm at a concentration of 15 mg/mL (Semwal et al. 2009).
 404 D.K. Semwal and R.B. Semwal

Gindarinine (3), in the form of nitrate, shows antibiotic activity against Staphylococcus
sp. (Chopra et al. 1958). The detailed methodology of this study is not well described in the
literature. Thus, herein it is being discussed partially. Glabradine (19), a hasubanalactam
alkaloid from the tubers, shows inhibitory activity against S. aureus, S. mutans, M. gypseum,
M. canis and T. rubrum superior to those of standards. The IZD values for 19 were measured to
be 18 – 27 cm at 100 mg/mL in each case whereas the MIC values were found to be 25– 50 mg/mL
when compared to those of novobiocin (IZD ¼ 21 –22 mm) and erythromycin (IZD ¼ 15–
20 mm) at a concentration of 15 mg/mL (Semwal & Rawat 2009a).
An herbal mixture of S. glabra (40 – 60 mg) together with Stephania venosa Spreng. (40 –
60 mg), Stephania suberosa Forman (40 –60 mg), Hedychium coronarium Roem (Zingiber-
aceae) (40 – 60 mg), Zingiber officinale Roscoe (Zingiberaceae) (30 – 50 mg) and Curcuma
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amada Roxb. (Zingiberaceae) (30 –50 mg) has been found effective for the prophylaxis and
treatment of AIDS in the form of dried powder filled in gelatine capsules. The formulation
was found to improve physical condition of AIDS patients, and it could be alleviated or cease
the symptoms of most opportunistic infections. Since the mixture comprises all well-known
non-toxic medicinal herbs, hence, its use can be safe for human beings (Kongpitak &
Kenneth 1999).

6.5. Anthelmintic activity

An alcoholic extract obtained from the rhizomes exhibits anthelmintic activity against four
nematodes: Heterakis gallinarum, Ascaridia galli, Ancylostoma ceylanicum and Ascaris suum;
one cestode: Raillietina echinobothrida, and one trematode: Fasciolopsis buski at the doses
ranging from 25 to 100 mg/mL in 0.9% phosphate buffered saline. The remarkable activity was
observed against R. echinobothrida and F. buski, and gradual decline in their physical motility
was recorded (Das et al. 2004). The crude aqueous extract and purified fractions obtained from
the rhizomes show potent vermicidal activity against R. echinobothrida, a parasitic tapeworm
responsible for nodular tapeworm disease in poultry. The crude extract increases the NO
synthase activity and cyclic guanosine monophosphate (cGMP) up to 87% and 103%,
respectively, and also increases NO efflux by 2– 3 fold at the time of onset of paralysis in the
parasites in comparison with their controls. The activity was considered as strong when
compared with those of anthelmintic agents: genistein, sodium nitroprusside and praziquantel (a
standard drug). This research suggested that tetrahydropalmatine (1) disturbs the downstream
signalling pathway of NO, as shown by the change in cGMP concentration in the tissues of
R. echinobothrida (Das et al. 2009). A further study by the same group (Das et al. 2013) found
that 1 together with other alkaloids inhibits the activity of phosphoenolpyruvate carboxykinase,
an important regulatory enzyme of glycolysis in R. echinobothrida in contrast to its role in
gluconeogenesis in their host, domestic fowl. An aqueous extract from the rhizomes of S. glabra
and its equimolar mixture with root extract of T. multiloba Miq. (Cucurbitaceae) show onset of
paralysis in A. ceylanicum, a hookworm obtained from the intestine of golden hamsters
(Mesocricetus auratus) with a concentration of 100 mg/mL in both cases. The activity of the
combined extract was found superior than that of S. glabra itself. S. glabra extract shows
paralysis in the parasites in 5.26 h, whereas the combined extract shows paralysis only in 2.71 h,
which was found almost similar to that of standard, mebendazole (2.5 h) at a concentration of
10 mg/mL (Tandon et al. 2004; Lyndem et al. 2008).

6.6. Anti-diabetic activity

An ethanolic extract from the tubers shows anti-hyperglycaemic activity in alloxan-induced
diabetic mice at oral administration of 500 mg/kg body weight. It reduces the total blood sugar in
 Natural Product Research 405

mice by 53% after 24 h, whereas glibenclamide (a standard antidiabetic agent) shows reduction
by 54% at a dose of 25 mg/kg, p.o. (Semwal, Rawat, Badoni, et al. 2010). 11-Hydroxypalmatine
(21), derived from the tubers, exerts hypoglycaemic effect against alloxan-induced diabetic mice
with total reduction in the blood glucose level of test group by 52% at a dose of 100 mg/kg, p.o.
body weight in comparison with diabetic control (27%) and positive control glibenclamide (54%
at 25 mg/kg) groups after 24 h of treatment (Semwal, Rawat, Semwal, et al. 2010).

6.7. Anti-allergic activity

A methanolic extract from the tubers shows H1-receptor antagonist or histamine antagonist
activity on in vitro models of guinea pig ileum and goat tracheal chain preparation, and could be
used to treat allergies. The extract at a concentration of 100 mg/mL was shown to have activity
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by blocking histamine-induced contraction in goat trachea and guinea pig ileum by 64% and
60%, respectively, whereas chlorpheniramine, a standard at a concentration of 10 mg/mL, shows
inhibition in contractions by 51% and 54%, respectively (Khan et al. 2010).

6.8. Anti-inflammatory, analgesic and antipyretic activities

An intraperitoneal administration of cycleanine (4) at a dose of 50 mg/kg shows anti-
inflammatory activity, and also reduces the vascular permeability and serum hyaluronidase
activity in rats, while it produces no activity in adrenalectomised rats (Rastogi & Mehrotra
1991b). Gindarudine (20), a morphine alkaloid, shows remarkable analgesic and antipyretic
activities on in vivo models of albino mice and Brewer’s yeast-induced pyrexia rats,
respectively. An oral administration of 20 with a highest dose of 150 mg/kg body weight shows
analgesic effects by increasing the threshold potential of pain in mice, while a maximum oral
dose of 300 mg/kg exhibits antipyretic activity by decreasing the rectal temperature of rats
within 1 h of treatment. The analgesic activity was compared with aspirin (300 mg/kg, p.o.),
whereas antipyretic activity was compared with paracetamol (200 mg/kg, p.o.) (Semwal et al.
2011).

6.9. Antitumour activity

Cycleanine (4) was found to have an antitumour potential. It showed in vitro cytotoxicity against
cultured HeLa cells with an ED50 value of 12 mg/mL, whereas against HeLa-S3 cells, it did not
show any effect. The compound was also studied for its in vivo antitumour activity against
ascites tumour from Ehrlich ascites carcinoma and solid tumour from Sarcoma-180 in mice, but
no activity was noticed up to 125 mg/kg/day (Kuroda et al. 1976).

7. Toxicity studies
An ethanolic extract obtained from the tubers of S. glabra was studied to evaluate its toxicity
including lethality or death in mice. The LD50 value was assessed by administering different oral
doses, i.e. 100, 200, 500 and 1000 mg/kg, body weight, of the extract to mice, and were observed
after a regular interval up to 21 days for any toxic sign. The extract, up to 1000 mg/kg, body
weight, was found to be safe for further clinical studies (Semwal, Rawat, Badoni, et al. 2010).
Gindarine (1), an isoquinoline alkaloid isolated from the tuber of Soviet plant S. glabra, is
documented as a natural tranquilliser in Russia. Like other tranquillisers, at a higher dose, it may
cause long-term sedation and even induce mental and physical complaints. A clinical study
proved that gindarine (1) shows some toxic effects on pregnant rats. Hence, this alkaloid has
been considered as a moderate toxic, and a serious concern has been recommended before its use
for clinical trials (Arzamastsev et al. 1983). An intragastric administration of 1 to rats with doses
 406 D.K. Semwal and R.B. Semwal

of 20 and 60 mg/kg/day for 3 months exhibits the changes in functions of CNS, liver and blood.
Although the doses up to 50 mg/kg/day of 1 do not exhibit any allergising, mutagenic or
teratogenic effects in rats, its administration produces noticeable embryotoxic effect on the 1st to
20th day of pregnancy in rats. This preclinical toxicity study on rats demonstrates that 1 should
be strictly contraindicated in pregnancy (Arzamastsev et al. 1983).
An intravenous administration of stepharine (2) with 245 mg/kg, body weight, has been
considered as a minimal lethal dose for mice (Rastogi & Mehrotra 1991b). Mice and rats were
orally administered with gindarudine (20) at doses of 100, 250 and 500 mg/kg/day body weight,
and kept under regular observation for 12 days to evaluate the toxicity. The maximum dose, i.e.
500 mg/kg, was found to be safe for further uses because no toxic sign such as behavioural
changes and lethality was observed during the entire experimental period (Semwal et al. 2011).
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8. Cultivation
As a result of increasing demand of S. glabra for medicinal purpose, the plant is being
extensively explored. Therefore, the plant species is marked as endangered in several places of
its occurrence (Chhetri, Basnet, et al. 2005). Popov (1985) achieved a process of somatic
embryogenesis and plant development on the tissue culture of S. glabra, whereas Davydenkov
et al. (1988) qualitatively determined the presence of stepharine (2) in various cell cultures of the
plant. Afterward, Shamina et al. (1994) developed a method to improve the productivity of these
plant tissue cultures for further use. Titova et al. (2012) suggested a scale-up scheme for the
cultivation of this plant on a commercial scale. They used different strains of a suspension
culture of the plant grown in flasks and bioreactors, and compared those according to their
growth and accumulation of stepharine (2). It has been observed that a total of 19– 21 g/L dry
mass accumulates for the cultivation in flasks, which contains a total of 0.30 –0.35% of 2.
Moreover, bubble bioreactors were found useful for submerged cultivation which accumulates a
total of 11– 16 g/L dry biomass, having 0.05 –0.16% of 2. The use of such methods can be
implemented by cultivating the plant in nurseries or gardens to fulfil the demand of this
important plant without disturbing the ecosystem and environment.

9. Conclusionary remarks and future perspectives

It has been noticed that only tubers of the plant are phytochemically screened, no isolation report
has appeared in the literature showing the chemistry of other parts of the plant except for a report
on the qualitative determination of few alkaloids in leaves and stems (Bhakuni & Gupta 1982).
The isolation from these parts including flowers and fruits may produce some novel bioactive
leads in the near future. Moreover, if the chemical profiles of leaves, flowers or fruits of S. glabra
show similarity with those of tubers, certainly these regenerated parts will show similar medicinal
properties like the tuber, and any of them can be used for medicinal purpose in place of tubers
which can protect the plant from being over harvested. Other species of the genus Stephania such
as S. rotunda Lour., S. erecta Craib, S. abyssinica and S. pierrei Diels, containing similar
phytochemicals (bisbenzylisoquinoline and tetrahydroprotoberberine alkaloids), show remarkable
antimalarial activities against Plasmodium berghei and Plasmodium falciparum (Likhitwitaya-
wuid, Angerhofer, Chai, et al. 1993; Likhitwitayawuid, Angerhofer, Cordell, et al. 1993; Muregi
et al. 2004; Chea et al. 2007). However, S. glabra has not undergone such studies neither in vitro
nor in vivo, hence, this is a large and interesting field waiting for future researches.
Numerous traditional medicinal activities such as anti-diabetic, antipyretic, analgesic, anti-
inflammatory, antimicrobial and anti-parasitic have been scientifically validated. However, there
are several more traditional activities remaining to be validated scientifically. In traditional
medicine, S. glabra has been used for the treatment of cancer, but no scientific evidence is yet
 Natural Product Research 407

available. Furthermore, various other species of the genus Stephania containing similar alkaloid
constituents, such as S. cepharantha Hayata and S. venosa (Blume) Spreng, have shown potent
activity against various human cancer cell lines, including breast adenocarcinoma SKBR3 and
ovarian SKOV3 cells (Nakaoji et al. 1997; Moongkarndi et al. 2004; Montririttigri et al. 2008).
Nevertheless, this plant, neither in the form of a crude extract nor its isolates, except cycleanine
(4), has been evaluated for its anticancer efficacy. Hence, the plant itself or its constituents could
produce a novel anticancer agent in the near future. This hypothesis can be further correlated to
the presence of bisbenzylisoquinoline alkaloids in the plant, which are well known for their
anticancer activity (Kuroda et al. 1976) and also for the presence of aporphine alkaloids which
are recently considered as anticancer molecules (Semwal & Semwal 2013).
The plant is extensively used in folk medicine in Asian countries, especially for diabetes.
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However, the therapeutic index and safety index of this plant are not yet established. Therefore,
it is an urgent need to determine its therapeutic index and safety index so that the plant can be
used in traditional medicine without producing any toxic effect. Finally, on the basis of the
available knowledge about S. glabra, we may conclude that this plant has a great potential as a
source of natural health products in the near future.

Funding
The authors thank UGC, New Delhi, for financial assistance under Dr D.S. Kothari Postdoctoral Fellowship
Scheme [grant number F.4-2/2006(BSR)/13-321/2010(BSR)].

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