ARTICLE IN PRESS

Phytomedicine 12 (2005) 305–317

www.elsevier.de/phymed

Bacopa monniera, a reputed nootropic plant: an overview

A. Russoa,, F. Borrellib
a
Department of Biological Chemistry, Medical Chemistry and Molecular Biology, University of Catania, Catania, Italy
b
Department of Experimental Pharmacology, University of Naples ‘Federico II’, Naples, Italy

Received 22 October 2003; accepted 15 December 2003

Abstract
Bacopa monniera (BM), a traditional Ayurvedic medicine, used for centuries as a memory enhancing, anti-
inflammatory, analgesic, antipyretic, sedative and antiepileptic agent. The plant, plant extract and isolated bacosides
(the major active principles) have been extensively investigated in several laboratories for their neuropharmacological
effects and a number of reports are available confirming their nootropic action. In addition, researchers have evaluated
the anti-inflammatory, cardiotonic and other pharmacological effects of BM preparations/extracts. Therefore, in view
of the important activities performed by this plant, investigation must be continued in the recently observed actions
described in this paper. Moreover, other clinical studies have to be encouraged, also to evidence any side effects and
possible interactions between this herbal medicine and synthetic drugs.
r 2004 Elsevier GmbH. All rights reserved.

Keywords: Bacopa monniera; Ayurvedic; Saponins; Nootropic action; Antioxidant activity

Introduction
Cerebral abilities have been observed to diminish
significantly with advancing age and factors such as
emotional stress could precipitate these effects.
While pharmaceutical companies continue to invest
enormous resources in identifying agents that could be
used to alleviate debilitating disorders and retard mental
deterioration afflicting numerous people around the
world, a source of potentially beneficial agents, namely
phytochemicals, would appear to have significant
benefits that have yet to be fully exploited. Therefore,
several plants have been selected based on their use in
traditional systems of medicine, and research has
identified a number of natural compounds that could
Corresponding author. Tel.: +39 095 7384073;
fax: +39 095 7384220.
E-mail address: alrusso@unict.it (A. Russo).
act as nootropic agents. One plant that has been used as
brain tonic and restorative in debilitated conditions is
Bacopa monniera (BM). BM, family Scrophulariaceae, is
a creeping annual plant found throughout the Indian
subcontinent in wet, damp and marshy areas (Chune-
kar, 1960; Satyavati et al., 1976). This medicinal plant is
locally known as Brahmi. The name Brahmi is derived
from the word ‘‘Brama’’, the mythical ‘‘creator’’ in the
Hindu pantheon. Because the brain is the centre for
creative activity, any compound that improves the brain
health is called Brahmi.
BM has been used by Ayurvedic medical practitioners
in India for almost 3000 years and is classified as a
medhyarasayana, a drug used to improve memory and
intellect (medhya). The earliest chronicled mention of
BM is in several ancient Ayurvedic treatises including
the Caraka Samhita (6th century A.D.), in which it is
recommended in formulations for the management of a
range of mental conditions including anxiety, poor

0944-7113/$ - see front matter r 2004 Elsevier GmbH. All rights reserved.
doi:10.1016/j.phymed.2003.12.008
 ARTICLE IN PRESS
306 A. Russo, F. Borrelli / Phytomedicine 12 (2005) 305–317
cognition and lack of concentration, and the Bravpra-
kash Var-Prakarana (16th century A.D.). Brahmi is
currently recognized as being effective in the treatment
of mental illness and epilepsy. After clinical trials in
human volunteers, a chemically standardized extract of
BM has now been made available for clinical use by the
central Drug Research Institute in India (Dhawan and
Singh, 1996).
In certain parts of India, Brahmi is believed to be an
aphrodisiac; in Sri Lanka, under the name of Loonoo-
weella, Brahmi is prescribed for fevers; in the Philip-
pines, it is used as a diuretic (Uphof, 1968).
Botanical aspects
Family: Scrophulariaceae
The genus Bacopa includes over 100 species of aquatic
herbs distributed throughout the warmer regions of the
world. In the United States, the herbs are recognized as
weeds in rice fields and found growing abundantly in
marshes and wetlands of warmer regions (Barrett and
Strother, 1978).
BM is a small herb with purple flowers. It grows in
wet and sandy areas and near streams in tropical
regions. It is a creeping herb with numerous branches
and small fleshy, oblong leaves. Flowers and fruits
appear in summer. The stem and the leaves of the plant
are used (Mathew, 1984).
Salient botanical features
Stem: prostrate, (sub)succulent, herbaceous; leaves:
decussate, simple, oblong, 1
0.4 cm, succulent, punc-
tuate, penninerved, margin entire, apex obtuse, sessile;
flower: axillar, solitary, bracteate, linear, pedicel to
0.5 cm, purple in colour; calyx: 5 lobes (unequal); outer 2
lobes larger, oval, 7
3.5 mm; inner 2 lobes linear,
5.5
0.7 mm; median 1 lobe oblong, 5.5
2 mm, im-
bricate, (sub)succulent, punctuate, obtuse, acute; cor-
olla: white with violet and green bands inside the throat,
0.8 cm across, 5 mm tube; 5 lobes, obscurely 2-lipped,
2+3, (sub)equal, obtuse or emarginated; stamens: 4,
didynamous; filament pairs 1 and 2.5 mm anthers
oblong, contiguous, 1.5 mm; ovary: oblong-globose,
2 mm; style slightly deflexed, 5.5 mm; stigma flat capsule,
oblong-globose, 5
2.5 cm septicidal or locilicidal or 4
valved.
Synonyms for BM wettst.
(1) B. monniera (L.) Pennell yes
(2) Lysimachia monnieri L. Cent.
(3) Graticola monnieri L.
(4) Monniera cunefolia Michaux
(5) Herpestis monniera L. Kunth.
Chemical constituents
In view of the importance of this plant in the
indigenous system of medicine, systematic chemical
examinations of the plant have been carried out by
several groups of researchers. Detailed investigations
were first documented in 1931, when Bose and Bose
reported the isolation of the alkaloid ‘‘brahmine’’ from
BM. Later, other alkaloids like nicotine and herpestine
have also been reported (Chopra et al., 1956). The
isolation of D-mannitol, and a saponin, hersaponin and
potassium salts by Sastri et al. (1959) provided further
details of the chemical components of BM.
The major chemical entity shown to be responsible for
the memory-facilitating action of BM, bacoside A, was
assigned as 3-(a-L-arabinopyranosyl)-O-b-D-glucopyra-
noside-10, 20-dihydroxy-16-keto-dammar-24-ene (Chat-
terji et al., 1965). Bacoside A usually co-occurs with
bacoside B, the latter differing only in optical rotation
and probably an artefact produced during the process of
isolating bacoside A (Rastogi, 1990). The chemical
composition of bacosides, contained in the polar fraction,
has been established on the basis of chemical and physical
degradation studies. On acid hydrolysis, bacosides
yield a mixture of aglycones, bacogenin A1, A2, A3
(Kulshreshtha and Rastogi, 1973, 1974; Chandel et al.,
1977), which are artefacts, and two genuine sapogenins,
jujubogenin and pseudojujubogenin (Rastogi et al.,
1994). Another bacogenin, A4 was identified as ebelin
lactone pseudojujubogenin (Rastogi et al., 1994). Succes-
sively, a minor saponin bacoside A1 was isolated and
characterized as 3-O-[a-L-arabinofuranoyl(1-3)-b-L-ara-
binopyranosyl]jujubogenin (Rastogi et al., 1994). Rastogi
et al. (1994) evidenced a new triperpenoid saponin,
bacoside A3. Its structure was established as 3-b-[O-b-D-
glucopyranosyl(1-3)-O-[a-L-arabinofuranosy(1-2)]-O-
b-D-glucopyranosyl)oxy] jujubogenin by chemical and
spectral analyses. Garay et al. (1996a) isolated from
BM three new dammarane-type triterpenoid saponins
of biological interest, bacopasaponins A, B and C,
identified as 3-O-a-L-arabinopyranosyl-20-O-a-L-arabino-
pyranosyl-jujubogenin, 3-O-[a-L-arabinofuranosyl (I-2)
a-L-arabinopyranosyl]pseudojujubogenin and 3-O-[b-
D-glucopyranosyl(1-3){a- L-arabinofuranosyl(1-2)}a-L-
arabinopyranosyl]pseudojujubogenin by spectroscopic
and chemical transformation methods. The hitherto
undetermined configurations at C-20 and C-22 of
pseudojujubogenin were elucidated by phase-sensitive
ROESY, and 1H and 13C signals of the saponins were
assigned by DEPT, 1H–1H COSY, HSQC and HMBC
techniques. Successively, the same authors (Garay et al.,
1996b) isolated a new dammarane-type pseudojujubo-
genin glycoside, bacopasaponin D, defined as 3-O-[a-L-
arabinofuranosyl(I-2)b-D-glucopiranosyl]pseudojuju-
bogenin by spectroscopic and chemical transformation
methods. It is noteworthy that dammarane-type triter-
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A. Russo, F. Borrelli / Phytomedicine 12 (2005) 305–317
penoid saponins are major constituents of a number of
reputed herbal drugs, including ginseng. Although
jujubogenin glycosides have been isolated from several
reputed medicinal plants (i.e. Rhamnaceae and Scro-
phulariaceae), pseudojubogenin glycosides have only
been reported in this Indian herbal drug.
In view of the increasing interest on this herbal drug,
Chakravarty et al. (2001) undertook a thorough chemical
reinvestigation of the glicosidic fraction of the methanol
extract of the plant and were able to isolate two new
pseudojujubogenin glycosides designated as bacopaside I
and II. Their structures have been elucidated as 3-O-a-L-
arabinofuranosyl-(1-2)-[6-O-sulphonyl-b-D-glucopyrano-
sil-(1-3)]-a-L-arabinopyranosyl pseudojujubogenin and
3-O-a-L-arabinofuranosyl-(1-2)-[b-D-glucopyranosil-(1-
3)]b-D-glucopyranosyl pseudojujubogenin, mainly on the
basis of dimensional (2D) NMR and other spectral
analyses. Subsequently, the same authors (Chakravarty
et al., 2003) isolated three new saponins from BM,
designated as bacopasides III, IV and V, with structures
3-O-a-L-arabinofuranosyl-(1-2)-b-D-glucopyranosyl juju-
bogenin, 3-O-b-D-glucopyranosyl-(1-3)-a-L-arabinopyra-
nosyl jujubogenin, 3-O-b-D-glucopyranosyl-(1-3)-a-L-
arabinofuranosyl pseudojujubogenin, on the basis of
dimensional (3D) NMR and other spectral analyses.
In addition, Hou et al. (2002) have isolated a new
saponin, 3-O-[a-1-arabinofuranosyl-(1-2)]-a-L-arabino-
pyranosyl jujubogenin, named bacopasaponin G, a new
matsutaka alcohol derivative, (3R)-1-octan-3yl-(6-O-sulfo-
nyl)-b-D-glucopyranoside, a new phenylethanoid glycoside,
3,4-dihydroxyphenylethyl alcohol (2-O-feruloyl)-b-D-glu-
copyranoside, and a new glycoside, phenylethyl alcohol [5-
O-p-hydroxybenzoyl-b-D-apiofuranosyl-(1-2)]-b-D-gluco-
pyranoside.
Moreover, three new phenylethnoid glycosides, viz.
monnierasides I–III along with the known analogue
plantainoside B have been isolated from the glycosidic
fraction of BM (Chakravarty et al., 2002).
In Fig. 1, the chemical structure of some saponins
isolated from BM are reported.
Biological activity
The biological effects of BM are documented in
traditional as well as scientific literature. The most
important of these are the effects of the plant, plant
extracts and isolated bacosides on cognition and
memory functions, their anxiolytic effects and their role
in management of convulsive disorders.
Neuropharmacological activity
Beneficial effects on learning and memory
The plant, plant extracts and isolated bacosides have
been extensively investigated in several laboratories for
307
their neuropharmacological effects and a number of
reports are available confirming their nootropic action.
Preliminary studies established that the treatment
with the plant (Malhotra and Das, 1959) and with the
alcoholic extract of BM plant (Singh and Dhawan,
1982) enhanced learning ability in rats. Subsequent
studies indicated that the cognition-facilitating effect
was due to two active saponins, bacosides A and B,
present in the ethanol extract (Singh and Dhawan,
1992). These active principles, apart from facilitating
learning and memory in normal rats, inhibited the
amnesic effects of scopolamine, electroshock and
immobilization stress (Dhawan and Singh, 1996). The
mechanism of these pharmacological actions remains
conjectural. It has been suggested that the bacosides
induce membrane dephosphorylation, with a concomi-
tant increase in protein and RNA turnover in specific
brain areas (Singh et al., 1990). Further, BM has been
shown to enhance protein kinase activity in the
hippocampus which could also contribute to its noo-
tropic action (Singh and Dhawan, 1997). A study of
Bhattacharya et al. (1999) reported that a standardized
bacoside-rich extract of BM, administered for 2 weeks in
rats, reversed cognitive deficits induced by intracereb-
roventricularly administered colchicines and by injection
of ibotenic acid into the nucleus basalis magnocellularis.
The central cholinergic system is considered the most
important neurotransmitter involved in the regulation of
cognitive functions. Cholinergic neuronal loss in hippo-
campal area is the major feature of Alzheimer’s disease
(AD) and enhancement of central cholinergic activity by
anticholinesterase is presently the mainstay of the
pharmacotherapy of AD-type senile dementia. Admin-
istration of BM for two weeks, also reversed the
depletion of acetylcholine, the reduction in choline
acetylase activity and the decrease in muscarinic
cholinergic receptor binding in the frontal cortex
and hippocampus, induced by neurotoxin, colchicines
(Bhattacharya et al., 1999).
It has been suggested that the behavioural effects of
cholinergic degeneration can be alleviated by a reduc-
tion in noradrenergic function (Sara, 1989). BM is
known to lower norepinephrine and increase 5-hydro-
xytryptamine levels in the hippocampus, hypothalamus
and cerebral cortex (Singh and Dhawan, 1997). BM may
thus, also indirectly, modify Ach concentrations,
through its influence on other neurotransmitter systems.
In a recent study, standardized extracts of BM and
Ginkgo biloba (GB) were used to evaluate the anti-
dementic and anticholinesterase activities in adult male
Swiss mice (Das et al., 2002). Antidementic activity was
tested against scopolamine (3 mg/kg ip)-induced deficits
in passive avoidance (PA) test. Three different extracts
of BM (30 mg/kg) and of GB (15, 30 and 60 mg/kg) were
administered daily for 7 days and 60 min after the last
dose of scopolamine, i.e. transfer latency time (TLT)
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308 A. Russo, F. Borrelli / Phytomedicine 12 (2005) 305–317

OH

OH OH
OH
O OH
O O O

O O
O
OH OH
O O
O O
O CH OH
OH O
OH O
O OH
O O O
O O
OH OH
OH OH
OH
CH OH CH OH
OH OH
OH

Bacosaponin A Bacosaponin B Bacosaponin C

OH
OH OH

O
O O

O
O
O
OH
O OH O
OH O O
O
HO SO O O OH O
O HO O
O
OH O
O OH
O OH OH
OH
OH OH O
OH O OH
OH OH OH
OH
OH OH
OH
OH

Bacopaside I Bacopaside II Bacopaside IV

OH
OH OH

O O
O

O O O
CH OH
OH
O O
O O O
OH
O OH O
OH
OH
O OH
OH O
OH O
OH OH O
HOH C O
OH
OH
OH HO

OH

Bacopaside V Bacopasaponin D Bacosaponin G

Fig. 1. Chemical structure of some saponins isolated from BM.

and no transfer response (NTR) were taken as criteria that, unlike the amnesic action of benzodiazepine
for learning. BM and GB treatments produced sig- anxiolytics, BM promotes cognition. One study, using
nificant increases in TLT (Fig. 2) and NTR (Fig. 3), thus experimentally validated rat models of clinical anxiety,
attenuating the dementic effect. All the extracts showed compared to the anxiolytic effect of standardized BM
a dose-dependent inhibitory effect on acetylcholinester- extract with that of benzodiazepine. The effects of BM
ase/AchE activity in vitro, but none of BM extracts extract at levels of 5, 10, and 20 mg/kg administered
showed more than 50% inhibition, suggesting that the orally to rats were compared to those elicited by
extracts of GB and BM have potent cognitive enhancing lorazepam (LZP) (0.5 mg/kg administered intraperito-
properties, but with different mechanisms of action. neally). The higher doses of BM extract produced
significantly greater anxiolytic effects compared to
Anxiolytic effect LZP, a standard benzodiazepine (Tables 1 and 2)
The current interest in the anxiolytic properties of BM (Bhattacharya and Ghosal, 1998). However, BM has a
extract assumes greater relevance in view of the fact distinct advantage over LZP since it does not induce
 ARTICLE IN PRESS
A. Russo, F. Borrelli / Phytomedicine 12 (2005) 305–317 309

Fig. 2. Comparative antidementic effect of GB extract and three different extracts of BM at 30 mg/kg po on TLT in single-trial PA
test, significant difference from first trial, *po0:001: Scopolamine (3 mg/kg ip) 5 min prior to first trial in all the groups except
control (vehicle-treated) to induce dementia (no significant increase in TLT on second trial).

Fig. 3. Comparative antidementic effect of GB extract and three different extracts of BM at 30 mg/kg po on the percent NTR
parameter in single-trial PA test, significant difference in second trial from dementia group, *po0:05: Dementia and control groups
are the same as in Fig. 2.

amnesia and has, instead, a memory-promoting action
in animals and man (Singh and Dhawan, 1992; Dhawan
and Singh, 1996). These results were confirmed by
Shanker and Singh (2000) who reported that BM extract
possessed an anxiolytic effect.
Antidepressant activity
More recently, the standardized methanolic extract of
BM was investigated for potential antidepressant
activity in rodent models of depression. The effect was
compared with the standard antidepressant drug imi-
pramine (15 mg/kg ip). When given in the dose of 20 and
40 mg/kg, orally once daily for 5 days, the extract was
found to have significant antidepressant activity in
forced swim and learned helplessness models of depres-
sion and was comparable to that of imipramine (Sairam
et al., 2002).
Anticonvulsive action
Another important use of BM in traditional medicine
is anticonvulsive action, as reported in different experi-
mental studies. Shanmugasundaram et al. (1991) have
reported that the crude water extract of BM controls
epilepsy in experimental animals. Successively, BM
was studied in mice and rats, at oral doses ranging
between 1 and 30 g/kg, for its effect on the central
nervous system. The test material was studied for its
effect on pentobarbitone hypnosis, motor co-ordination,
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310 A. Russo, F. Borrelli / Phytomedicine 12 (2005) 305–317

Table 1. Effects of BM and LZP on the open-field test in rats (data are means7SEM)

Groups (mg/kg) n Squares crossed (N) Immobility (s) Rears (N) Faecal pellets (N)

Control (vehicle) 14 123.479.8 29.475.8 21.373.5 5.270.9

BM (5, p.o.) 8 193.778.5 23.272.8 28.474.0 4.470.8
BM (10, p.o.) 8 166.278.3* 18.473.6* 36.373.2* 3.170.7*
BM (20, p.o.) 8 176.276.6* 18.972.6* 44.273.3* 2.470.6*
LZP (0.5, i.p.) 8 169.474.9* 16.372.0* 38.172.6* 3.070.8*

*po0:05 different from control group.

Table 2. Effects of BM and LZP on the elevated plus-maze test in rats (data are means7SEM)

Groups n Total time spent on Total entries on % time spent on % entries on open
both open and both open and open arms (s) arms (N)
closed arms (s) closed arms (N)

Control (vehicle) 15 229.4716.8 23.271.4 22.974.0 36.274.6

BM (5, p.o.) 8 216.0712.3 27.972.6 31.674.8 45.475.1
BM (10, p.o.) 8 239.6711.2 27.472.9 46.473.9* 53.674.4*
BM (20, p.o.) 8 239.579.6 30.374.2 59.473.9* 66.272.8*
LZP (0.5, i.p.) 6 232.0710.1 29.673.4 53.973.5* 68.773.8*

*po0:05 different from control group.

tail-withdrawal reaction time, electroshock, chemocon- Antioxidant activity

vulsions, haloperidol-induced catalepsy and conditioned
avoidance response. The natural material exhibited a
sedative effect and significantly prolonged the hypnotic
action of pentobarbitone. It produced a variable
blockage of conditioned avoidance response. The
presence of a significant antinociceptive effect, coupled
with the ability of BM to offer protection against
electroshock seizures and chemoconvulsions plus the
ability to antagonize haloperidol-induced catalepsy,
suggests an involvement of the GABA-ergic system in
the mediation of central nervous system effects of BM
(Singh et al., 1996). Substances which stimulate GABA
are known to possess anticonvulsant, pain relieving and
sedative effects (Shanker and Singh, 2000).
On the basis of these studies, BM was evaluated
alone and in combination with phenytoin (PHT) (one
of the widely used anticonvulsants known to adver-
sely affect cognitive function), for its effect on PA
task, maximal electroshock seizures and locomotor
activity in mice (Vohora et al., 2000). PHT adversely
affected cognitive function in the PA task. BM reversed
PHT-induced impairment (Tables 3 and 4). Both
acquisition and retention of memory showed improve-
ment without affecting PHT anticonvulsivant activity.
Further investigations using BM alone or in com-
bination with other antiepileptic drugs are warranted
to explore the full potential of BM in epilepsy and
in correcting antiepileptic drug-induced cognitive
impairment.
Data from different laboratories suggest that the
cognition-promoting functions of BM may be partially
attributed to the antioxidant effects of the bacosides.
One study determined the effects of alcohol and hexane
extract of BM on lipid peroxidation by ferrous sulphate
and cumene hydroperoxide in rat liver homogenate
(Tripathi et al., 1996). The alcohol fraction exhibited a
greater protection against both inducers. The results
were also compared with known antioxidants, tris (2-
amino-2-hydroxymethyl-1,3-propanediol) a hydroxyl
trapper, EDTA, a metal chelator, and the natural
antioxidant, vitamin E (100 mg of the alcoholic extract
of BM was equivalent to 247 mg of EDTA and 58 mg of
vitamin E). EDTA and Vitamin E, offered dose-
dependent protection against ferrous sulphate-induced
peroxidation, BM only slightly protected against the
oxidation of reduced glutathione suggesting that BM
mechanism of antioxidant action could be attributed to
metal chelation at the initiation level of the free radical-
induced chain reaction or to the quenching of free
radicals at propagation level.
A more recent study explored the effect of BM extract
on the rat brain frontal cortical, striatal, and hippo-
campal superoxide dismutase (SOD), catalase (CAT)
and glutathione peroxidase (GPX) activities, following
administration for 7, 14 or 21 days (Bhattacharya et al.,
2000). The results were compared with the effect
induced by deprenyl, a well-known neurological anti-
Table 3. Effect of phenytoin, BM extract and their combination (chronic treatment) on acquisition and retention performance in a passive-avoidance paradigm in mice

Treatments (per Trials required Retention (2 h) Retention (24 h)

kg po; n ¼ 10) for acquisition
(number)
SDL (s) SDE (number) TSZ (s) SDL (s) SDE (number) TSZ (s)

Distilled water 3.470.25 189.9732.40 4.270.487 51.3710.02 424.0745.69 1.070.24 6.473.07

(10 ml
14 days)
PHT (25 mg
14 4.770.20*** 60.8715.52** 6.871.33b 259.1757.23c** 101.4710.61C*** 2.670.35C** 7.5730.37b*
days)
BM (40 mg
7 2.370.14d*** 203.0725.83d** 2.670.2** 28.972.53b* 489.0746.97b 0.770.24 1.070.28*
days)
PHT (25 mg
14 4.070.31 71.6712.70** 3.070.20* 74.1716.46 290.7754.85 1.170.17 11.275.23
days)+BM

A. Russo, F. Borrelli / Phytomedicine 12 (2005) 305–317

(40 mg
7 days)
a
PHT, phenytoin; BM, Bacopa monniera extract; SDL, step down latency; SDE, step-down errors; and TSZ, time in shock zone.
*po0.05.

ARTICLE IN PRESS
**po0.01.
***po0:001 versus control; b, po0:05; c, po0:01; d, po0:001 versus combined treatment. Significant by one-way ANOVA and students’s t-test.

Table 4. Effect of phenytoin, BM extract and their combination (chronic treatment) on maximal electroshock-induced seizure in mice

Sl. no. Treatment (per kg; po) n Duration (mean7SEM, s)

Flexion Extension Clonus Stupor

I Distilled water (10 ml
14 days) 10 1.270.12 13.070.51 8.670.69 210.775.10

II PHT (25 mg
14 days) 10 1.770.20* 0.070.00*** 16.571.05*** 98.9728.96**
III BM (40 mg
7 days) 10 1.270.12 12.570.74d 9.170.55d 201.577.30d
IV PHT (25 mg
14 days)+BM (40 mg
7 days) 10 1.670.21 0.070.00*** 16.870.85*** 89.6726.95***
V PHT (10 mg
14 days) 5 1.470.21 6.072.31 7.471.34 108.0713.20
VI PHT (25 mg
14 days)+BM (40 mg
7 days) 5 1.270.17 5.072.74 7.271.03 123.0728.75
a
n ¼ number of animals.
*po0.05.
**po0.01.
***po0.001 versus I; d: po0.001 versus IV (Significance by ANOVA and student’s t-test).

311
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312 A. Russo, F. Borrelli / Phytomedicine 12 (2005) 305–317
oxidant for the same time period. BM induced a dose-
related increase in SOD, CAT, and GPX activities in all
brain regions investigated, after treatment for 14 or 21
days. On the contrary, deprenyl induced an increase in
SOD, CAT, GPX activities in the frontal cortex and
striatum, but not in the hippocampus, after 12 or 21
days. Pawar et al. (2001) demonstrated that the
hydroalcoholic extract of the whole BM plant exhibited
an inhibitory effect on superoxide released from
polymorphonuclear cells in nitroblue tetrazolium assay.
The bacoside A3 was found to be responsible for this
effect.
Sumathy et al. (2001) investigated the hepato-
protective activity of BM alcohol extract, administered
orally, on the liver antioxidant status of morphine-
treated rats. The results obtained demonstrated that
coadmnistration of BM exerted a protective influence
against the inhibition of antioxidant enzymes and
reduction in GSH level in rats. Further, BM inhibited
the lipid peroxide formation of morphine administra-
tion, thereby clearly establishing its protective role in
morphine toxicity in rat liver. A more recent study,
affected by the same research group, indicated the
protective effect of BM extract on morphine-decreased
brain mitochondrial enzyme activity in rats (Sumathy
et al., 2002).
In a study to test the hypothesis that BM directly
decreases the production of free radicals, we used the
Paoletti assay, which excludes the Fenton-type reaction
and the xanthine–xanthine oxidase system (Russo et al.,
2003a). Our results indicate that BM is able to directly
inhibit the superoxide anion formation in a dose-
dependent manner. The free radical scavenging activity
of this methanolic extract was also evaluated through its
ability to quench the synthetic radical 1,1-diphenyl-2-
picryl-hydrazyl (DPPH). The free radical scavenging
capacity of BM, demonstrated in the Paoletti and in
DPPH tests, was confirmed by protection against
plasmid DNA strand scission, induced by  OH radicals,
generated from UV photolysis of H2O2. In fact, this
extract suppressed the formation of linDNA and
induced a partial recovery of scDNA. Moreover, this
extract exhibited a protective effect on H2O2-induced
cytotoxicity and DNA damage in human non-immorta-
lized fibroblasts.
There is growing evidence that high concentrations of
nitric oxide (NO), generated (enzymatically and non-
enzymatically) by activated astrocytes, might be involved
in a variety of neurodegenerative diseases, such as AD,
ischemia and epilepsy (Colasanti and Suzuki, 2000).
Therefore, a study was designed to examine the effect of a
methanolic BM extract on toxicity induced by the NO
donor, S-nitroso-N-acetyl-penicillamine (SNAP), in cul-
ture of rat astrocytes. The results indicated that after 18 h
of treatment, SNAP determined an increase in the
intracellular oxidants, as demonstrated by oxidation of
the marker 20 ,70 -dichlorodihydrofluorescein diacetate,
and caused a fragmentation of genomic DNA (examined
by COMET assay) compared to control astrocytes.
Methanolic extract of BM (3–6–12 mg/ml) added to the
cells during SNAP treatment, reduced the intracellular
oxidants, consequently preventing DNA damage (Russo
et al., 2003b).
Other biological effects
Besides mental functioning, Ayurvedic texts advocate
the use of BM in other physiological conditions. As a
result, researchers have evaluated the anti-inflamma-
tory, cardiotonic and other pharmacological effects of
BM preparations/extracts.
The effect of BM in inhibiting experimentally induced
inflammation was compared with that of indomethacin,
a known anti-inflammatory drug. The results of this
study showed that BM effectively suppressed experi-
mentally induced inflammatory reactions, by inhibiting
prostaglandin synthesis and partly by stabilizing lyso-
somal membranes, and did not cause gastric irritation at
anti-infiammatory doses (Jain et al., 1994).
Fresh BM juice (BMJ) has been reported to have
significant antiulcerogenic activity (Rao et al., 2000).
The antiulcerogenic effect of BMJ was examined using
gastric ulcer models induced by ethanol, aspirin, 2 h
cold-restraint stress and 4 h pylorus ligation. BMJ
100–300 mg/kg produced significant antiulcer activity
in all the experimental gastric ulcer models except in the
case of ethanol-induced ulcers where 100 mg/kg was not
found to have a significant effect. BMJ (100–300 mg/kg)
was found to have little or no effect on offensive
acid–pepsin secretion, while cell shedding and mucin
secretion in terms of total carbohydrates and protein
ratio (TC:P), the two important parameters of defensive
factors, respectively, decreased and increased signifi-
cantly, indicating enhancement of protective mucosal
factors. Both BMJ (300 mg/kg) and sucralphate, used as
the reference compound, showed a tendency to increase
the mucosal glycoproteins in terms of TC:P. Thus, ulcer
protective effect of BMJ may be due to its effect on
mucosal defensive factors such as enhanced mucin
secretion, mucosal glycoprotein and decreased cell
shedding, rather than on offensive factors such as acid
and pepsin. Moreover, Sairam et al. (2001) reported that
BME, standardized to bacoside A content, when given
in the dose of 10–50 mg/kg, twice daily for 5 days,
showed dose-dependent antiulcerogenic action on var-
ious gastric ulcer models induced by ethanol, aspirin, 2 h
cold-restraint stress, and 4 h pylorus ligation. BME
20 mg/kg showed no effect on acid–pepsin secretion,
but increased mucin secretion and decreased cell
shedding with no effect on cell proliferation. In the
same study, it was reported that BME effectively
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A. Russo, F. Borrelli / Phytomedicine 12 (2005) 305–317
alleviated stress-induced ulcers with a marked decrease
in LPO, increasing SOD and CAT activity. More
recently, Goel et al. (2003) reported that a standardized
BM extract in the dose of 1000 mg/ml showed anti-
Helicobacter pylori activity in vitro.
As stress is a factor in many diseases, research on an
effective antistress agent obtained from plants has gained
importance. Rai et al. (2003) have evaluated the effect of
a standardized extract of BM against acute (AS) and
chronic stress (CS) models in rats. Pretreatment with BM
at 40 mg/kg per os significantly reduced the AS-induced
changes in adrenal gland weight, spleen weight, plasma
glucose, alanine aminotransferase and aspartate amino-
transferase (AST). CS exposure resulted in a significant
increase in the ulcer index, adrenal gland weight, plasma
AST, and creatine kinase (CK) with a significant decrease
in thymus and spleen weight, plasma triglyceride, and
cholesterol. Pretreatment with low dose of BM extract at
40 mg/kg significantly reversed changes in ulcer index and
plasma AST only, whereas the pretreatment with higher
dose significantly reversed CS-induced changes in ulcer
index, adrenal gland weight, CK, and AST. On the basis
of these results, therefore, the authors suggested that the
standardized extract of BM possesses an adaptogenic
activity.
The anticancer nature of this plant extract was
reported in Walker carcinoma; a subsequent study
showed that BME significantly inhibited Sarcoma-180
cell growth in vitro (Elangovan et al., 1995).
Dar and Channa (1997a) demonstrated that BME
possessed relaxant properties in blood vessels and
tracheal preparations from rabbit and guinea-pigs with
a partial contribution by b-adrenoreceptors and pros-
taglandins. BM also produced bronchodilation in
anaesthetized rats (Dar and Channa, 1997b), supporting
the traditional use of this plant in folklore medicine for
various respiratory ailments (Chopra et al., 1956;
Nadkarni, 1976). This study demonstrated that the
BME possessed a bronchodilatatory property, clearly
reflected by antagonism of carbachol-induced effects on
inspiratory and expiratory pressures. Additionally, the
plant extract at 37 and 50 mg/kg also inhibited
carbachol-induced hypotension. The plant extract ex-
hibited a dual action on bronchoconstriction induced by
carbachol. At low doses (25 and 37 mg/kg), it predomi-
nantly inhibited inspiratory pressure, but at a high dose
(50 mg/kg) inhibited only expiratory pressure. This
property of the plant extract implies that more than
one mechanism of action may be responsible for
bronchodilation. Some of the possible mechanisms
include b-adrenoceptor activation, muscarinic receptor
antagonism, prostaglandin release or interference with
calcium mobilization. A more recent study by the same
authors demonstrates the calcium antagonistic activity
in ethanol extract of BM (Dar and Channa, 1999), as
reported in various groups of natural products such as
313
alkaloids (Yano et al., 1991), terpenes (Hwang et al.,
1987) and flavonoids (Di Carlo et al., 1999). The plant
extract inhibited the spontaneous movements of both
guinea-pig ileum (IC50 ¼ 2474 mg/ml) and rabbit jeju-
num (IC50 ¼ 13679 mg/ml). A marked reduction in
acetylcholine and histamine-induced responses in the
ileum was evident in the presence of extract (260 mg/ml).
Acetylcholine (1 mM)-induced contraction in the ileum
was also inhibited by the extract in a dose-dependent
manner. Calcium chloride-induced responses in rabbit
blood vessels and jejunum were attenuated in the
presence of plant extract (10–700 mg/ml) implying a
direct effect of the extract on the influx of calcium ions
into cells. However, the absence of any modification of
either noradrenaline or caffeine-induced contractions in
the presence of BM extract suggests that this natural
compound has no detectable effect on mobilization of
intracellular calcium. The author, therefore hypothe-
sized that the spasmolytic effect of BM extract in
smooth muscles is predominantly due to inhibition of
calcium influx via both voltage- and receptor-operated
calcium channels of the cell membrane. A recent study
by Channa et al. (2003) demonstrates that various
fractions and subfractions isolated from BM produced
significant inhibition of carbachol-induced bronchocon-
striction, hypotension and bradycardia in anaesthetized
rats, and that methanol fraction and CHCl3/MeOH
subfraction caused a marked reduction in calcium
chloride-induced contraction on guinea-pig ileum, in-
dicating their interference with Ca2+ ion movement.
In addition, it has been reported that BM methanolic
extract exhibited a potent activity comparable to
disodium cromoglycate, a known mast cell stabilizer,
indicating the potential usefulness of BM leaves in
allergic conditions (Samiulla et al., 2001).
Clinical studies
Supporting the preclinical investigations, several
clinical studies, summarized in Table 5, have been
carried out. Two singe-blind open clinical studies have
reported memory and learning enhancing effects of
chronic BM treatment in both patients with anxiety
neurosis (Singh and Singh, 1980) and in children
(Sharma et al., 1987). Therefore, BM has been
introduced onto the market in India and other
countries, alone or in association with other phytocom-
plexes, and utilized in the treatment of memory and
attention disorders (Shukia et al., 1987). The commer-
cial preparation has shown a remarkable nootropic
activity, above all in very young subjects (Dave et al.,
1993). After clinical trials on human volunteers, a
standardized extract of BM has now been made
available for clinical use by the Central Drug Research
Institute, Lucknow, India (Dhawan and Singh, 1996).
 ARTICLE IN PRESS
314 A. Russo, F. Borrelli / Phytomedicine 12 (2005) 305–317

Table 5. Clinical studies of BM

Substances/treatments Subjects/patients Results/comments References

BM crude extract; chronically
for 4 weeks
BM extract; chronically for
12 weeks
BM standardized extract
BM standardized extract
(300 mg); chronically for 12
weeks
BM standardized extract
(300 mg); acute treatment for
2h
BM standardized extract
(300 mg) combined with
Ginkgo biloba extract
(120 mg); acute treatment for
90 and 180 min
BM standardized extract
(300 mg); one trial after
chronic treatment for three
months and an other trial and
for 6 weeks after the
completion of the trial
Patients with anxiety neurosis
Children
Mentally retarded children
Healthy adult subjects
Healthy adult subjects
Healthy adult subjects
Healthy adult subjects
Enhancing of memory Singh and Singh (1980)
Enhancing memory and Sharma et al. (1987)
learning
Effective in enhancing Dave et al. (1993)
learning and in controlling
abnormal behaviour
Improving early information Stough et al. (2001)
processing, verbal learning
and memory consolidation
No significant changes were Nathan et al. (2001)
found
No acute effect on cognitive Maher et al. (2002)
was found on any of the tests
Significant effect on a test for Roodenrys et al. (2002)
retention of new information.
Tasks assessing attention,
verbal and visual short term
memory and the retrieval of
pre-experimental knowledge
were unaffected

Recently, Stough et al. (2001) undertook a study,
using a double-blind placebo-controlled design and a
battery of well-validated neuropsychological tests, to
examine the chronic effects of an extract of BM on
cognitive function in healthy human subjects. The
authors showed that BM (300 mg) given chronically
for 12 weeks improved early information processing,
verbal learning and memory consolidation in humans.
This is consistent with the study of Sharma et al. (1987),
who also observed positive effects on learning and
memory following 12 weeks administration. However,
as reported for GB extract (Nathan et al., 2002), no
acute effects on cognitive function were found at a lower
dose (300 mg) (Nathan et al., 2001), even when BM
extract was combined with GB extract (Maher et al.,
2002). Therefore, as suggested by the authors, it is
possible that the combined administration of both these
extracts chronically may exert more potent effects on
cognitive function.
Roodenrys et al. (2002), again based on behavioural
studies with rats, examined the effects of an extract of
BM on cognitive function. Seventy-six adults aged
between 40 and 65 years took part in a double-blind
randomized, placebo control study in which various
memory functions were tested and levels of anxiety
measured. The results showed a significant effect of
Brahmi on a test for the retention of new information.
Follow-up tests showed that the rate of learning was
unaffected, suggesting that it decreases the rate of
forgetting of newly acquired information. Tasks asses-
sing attention, verbal and visual short-term memory and
the retrieval of pre-experimental knowledge were
unaffected. Questionnaire assessments of every day
memory function and anxiety levels were also unaf-
fected.
Toxicological study
It has been found to be well tolerated and without any
untoward reaction or side effects in regulatory pharma-
cological and toxicological studies.
The LD50 of aqueous and alcoholic crude extracts of
BM in rats were 1000 mg and 15 g/kg by intraperitoneal
route, respectively (Martis et al., 1992). The aqueous
crude extract given orally at a dose of 5 g/kg did not
show any toxicity. The LD50 of the alcoholic crude
extract was 17 g/kg given orally.
The safety of pharmacological doses of isolated
bacosides has been tested in healthy, male, human
volunteers. A phase I single-dose tolerance study was
conducted in 31 healthy human volunteers. The trial was
double-blind, placebo controlled and non-crossover.
 ARTICLE IN PRESS
A. Russo, F. Borrelli / Phytomedicine 12 (2005) 305–317
The dose of bacosides A and B ranged from 20 to
300 mg (6 volunteers in placebo group and 4 each in 20,
50, 75, 100, 150, 200 mg group, respectively, only 1
volunteer received 300 mg of bacosides). A multiple dose
study was completed in 20 healthy human subjects. Ten
healthy human volunteers received 100 mg bacosides A
and B orally per day for 4 weeks, while 10 were given
200 mg bacosides A and B. A detailed pre- and post-
drug monitoring of clinical, haematological and bio-
chemical laboratory investigations did not reveal any
drug-related abnormality. Single as well as repeated
doses of bacosides A and B/ placebo were tolerated well,
no side effects were experienced by any subject. Thus
single doses of bacosides A and B (100 and 200 mg)
administered for 4 weeks have been tolerated well and
are devoid of any untoward reaction or side effects
(Singh and Dhawan, 1997).
Conclusion
BM, a traditional Ayurvedic medicinal plant has been
used for centuries as a memory-enhancing, anti-inflam-
matory, analgesic, antipyretic, sedative, and antiepilep-
tic agent. More recently, preclinical studies have
reported cognitive enhancing effects with various
extracts of BM, but the exact mechanism of its actions
is still uncertain, as its multiple active constituents make
its pharmacology complex. It has been suggested that
BM, like GB, exhibits neuroprotective and cognitive
enhancing effects, in part due to its, capacity to
modulate the cholinergic system (Bhattacharya et al.,
1999) and to contrast oxidative stress (Bhattacharya et
al., 2000; Russo et al., 2003a, b). Therefore, in view of
the important actions performed by this plant, further
research must be undertaken into the recent findings
described here.
Although pre-clinical animal studies have shown that
BM, like GB, has nootropic effects in established
learning and memory models, few clinical studies have
been performed to complement these findings. Litera-
ture data reported that BM given chronically improved
early information processing and verbal learning and
memory consolidation in humans (Stough et al., 2001).
However, as reported for GB extract (Nathan et al.,
2002), no acute effects on cognitive function were found
at a lower dose (Nathan et al., 2001), even when BM
extract was combined with GB extract (Maher et al.,
2002). As suggested by the authors, it is possible that the
combined administration of both these extracts chroni-
cally may exert more potent effects on cognitive
function. Therefore, other clinical investigations have
to be encouraged, also in order to evidence any possible
side effects. Different studies indicated that interactions
between herbal medicines and synthetic drugs exist and
315
can have serious clinical consequences (Izzo and Ernst,
2001). GB raised blood pressure when combined
with a thiazide diuretic and coma in a patient with
AD taking low-dose trazodone. It is therefore extremely
important to also consider the possibility of BM–drug
interaction.
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