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Efficacy and safety of Stephania glabra:an alkaloid-rich traditional medicinalplantDeepak Kumar Semwalab & Ruchi Badoni Semwalab

a Department of Chemistry, Panjab University, Chandigarh160014,Indiab Department of Pharmaceutical Sciences, Tshwane University ofTechnology, Pretoria0001, South AfricaPublished online: 04 Sep 2014.

To cite this article: Deepak Kumar Semwal & Ruchi Badoni Semwal (2015) Efficacy and safety ofStephania glabra: an alkaloid-rich traditional medicinal plant, Natural Product Research: FormerlyNatural Product Letters, 29:5, 396-410, DOI: 10.1080/14786419.2014.955487

To link to this article: http://dx.doi.org/10.1080/14786419.2014.955487

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REVIEW

Efficacy and safety of Stephania glabra: an alkaloid-rich traditionalmedicinal plant

Deepak Kumar Semwalab* and Ruchi Badoni Semwalab*

aDepartment of Chemistry, Panjab University, Chandigarh 160014, India; bDepartment of PharmaceuticalSciences, Tshwane University of Technology, Pretoria 0001, South Africa

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

Stephania glabra (Roxb.) Miers (Menispermaceae) has long been used for thetreatment of asthma, tuberculosis, dysentery, hyperglycaemia, cancer, fever, intestinalcomplaints, sleep disturbances and inflammation in many Asian countries. It mainlycontains alkaloids and, until now, over 30 alkaloids such as bisbenzylisoquinolines,hasubanalactams, berberines and aporphines have been isolated from its tuber. Most ofits traditional medicinal activities are scientifically approved by various in vitro andin vivo studies. It shows remarkable anti-psychotic, anti-diabetic, antipyretic, analgesic,antimicrobial and anti-hypertensive activities. This work includes comprehensiveinformation on the ethnobotany, chemistry and pharmacology of S. glabra. This reviewalso focuses on the future perspectives with main emphasis on the establishment oftherapeutic index and safety index of the plant. This review concludes that S. glabra hasa great potential to treat various diseases, and could be used as a source for novelhealthcare 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 2200m 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

q 2014 Taylor & Francis

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

Natural Product Research, 2015

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

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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 1–2mm 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

Figure 1. Flowering twig, fruits and tuber of S. glabra.

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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

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

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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

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)

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OHO

OHO

O

O

HH

H

HOOH

H OH

H

OH

OH

HO

OH

OCH3

NO

O

O

O HO

HO

O

OH

OCH3

NH

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

N

OCH3

OCH3

H3CO

H3CO

OCH3

H3CO

O

HO

N

OCH3

NH

OCH3

H3CO

HO

8-(4’-methoxybenzyl) xylopinine (22) Cepharamine (23) Tuduranine (24)

NR2

H3CO

R4

R5

R6

H

R3

R1

N

O

H3CO

H3COH R

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)

Stepholidine [R1=H, R2=OH, R3=H, R4=OCH3, R5=OH, R6=H] (12) Capaurine [R1=OH, R2=OCH3, R3=H, R4=OCH3, R5=OH, R6=H] (16)

Stepharine [R=H] (2) Pronuciferine [R=CH3] (10)

N+

R2O

R1O

OR5

OR4

R3

X-

X=Cl, I or NO3

N

HO

O

N

H3CO

H3CO

OCH3

OCH3

H

R

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) Stepharanine [R1=CH3, R2=H, R3=H, R4=H, R5=CH3] (8)

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)

Cycleanine [R=CH3] (4)N-Desmethylcycleanine [R=H] (15)

N+

H3CO

HO

HO

H3CON

O

ON

H3CO

H3CO

OCH3

OCH3

H

O

Magnoflorine (7) Roemerine (13) Corynoxidine (17)

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

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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 100mg/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 50mg/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 £ 105M/L against all

N

H3CO

HO

OH

OCH3

N

H3CO

HO

OH

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

NH2HO

OH

ONH

HO

HO

OH

OH

Tyrosine (27) Norlaudanosoline (28)

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

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tested agonists in 60min (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

220 nM in rats under general anaesthesia at intraperitoneal doses of 10 and 15mg/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

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 14.10mM. 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

N+ AChE [enzyme]

[H2O] HON+

O–

O

Acetylcholine

Figure 4. Hydrolysis of acetylcholine.

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6.2. Anti-hypertensive activity

Intravenous administration of L-stepholidine (12) with the doses of 0.5 and 2.5mg/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 witha dose of 5.50mg/kg, when administered intravenously. Phenoxybenzamine (2.5mg/kg) and

prazosin (1mg/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

in the striatum in rats at the doses of ,10mg/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 0.8M, 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 3M. However, the activity was considered to be mild when compared with

nifedipine (IC50 ¼ 0.03mM) (Martınez 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 10mg/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 25mg/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 10mg/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 28mm against bacterial and from

15 to 35mm against fungal pathogens at a concentration of 100mg/mL in each case. The MIC

values were found ranging from 25 to 100mg/mL against all test strains. The standard drugs

novobiocin (against bacterial species) and erythromycin (against fungal species) show IZD

values ranging from 12 to 25mm at a concentration of 15mg/mL (Semwal et al. 2009).

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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 100mg/mL in each case whereas the MIC values were found to be 25–50mg/mL

when compared to those of novobiocin (IZD ¼ 21–22mm) and erythromycin (IZD ¼ 15–

20mm) at a concentration of 15mg/mL (Semwal & Rawat 2009a).

An herbal mixture of S. glabra (40–60mg) together with Stephania venosa Spreng. (40–

60mg), Stephania suberosa Forman (40–60mg), Hedychium coronarium Roem (Zingiber-

aceae) (40–60mg), Zingiber officinale Roscoe (Zingiberaceae) (30–50mg) and Curcuma

amada Roxb. (Zingiberaceae) (30–50mg) 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 100mg/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 100mg/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

10mg/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 500mg/kg body weight. It reduces the total blood sugar in

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mice by 53% after 24 h, whereas glibenclamide (a standard antidiabetic agent) shows reduction

by 54% at a dose of 25mg/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 100mg/kg, p.o.

body weight in comparison with diabetic control (27%) and positive control glibenclamide (54%

at 25mg/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 vitromodels of guinea pig ileum and goat tracheal chain preparation, and could be

used to treat allergies. The extract at a concentration of 100mg/mL was shown to have activity

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 10mg/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 50mg/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 150mg/kg body weight shows

analgesic effects by increasing the threshold potential of pain in mice, while a maximum oral

dose of 300mg/kg exhibits antipyretic activity by decreasing the rectal temperature of rats

within 1 h of treatment. The analgesic activity was compared with aspirin (300mg/kg, p.o.),

whereas antipyretic activity was compared with paracetamol (200mg/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 12mg/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 125mg/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 1000mg/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 1000mg/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

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of 20 and 60mg/kg/day for 3 months exhibits the changes in functions of CNS, liver and blood.

Although the doses up to 50mg/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 245mg/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 500mg/kg/day body weight,

and kept under regular observation for 12 days to evaluate the toxicity. The maximum dose, i.e.

500mg/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).

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

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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.

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 FellowshipScheme [grant number F.4-2/2006(BSR)/13-321/2010(BSR)].

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