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Evidence-Based Complementary and Alternative Medicine
Volume 2012, Article ID 946259, 8pages
doi:10.1155/2012/946259
Review Article
Centella asiatica
(L.) Urban: From Traditional Medicine to
Modern Medicine with Neuroprotective Potential
Ilkay Erdogan Orhan1, 2
1Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey
2Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmacy, Eastern Mediterranean University,
Gazimagosa, (Famagusta), Cyprus
Correspondence should be addressed to Ilkay Erdogan Orhan, iorhan@gazi.edu.tr
Received 14 January 2012; Revised 27 February 2012; Accepted 6 March 2012
Academic Editor: Mahmud Tareq Hassan Khan
Copyright © 2012 Ilkay Erdogan Orhan. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
This paper covers the studies relevant to neuroprotective activity of Centella asiatica (L.) Urban, also known as “Gotu Kola.” The
plant is native to the Southeast Asia and has been used traditionally as brain tonic in ayurvedic medicine. The neuroprotective
effect of C. asiatica has been searched using the key words “Centella, Centella asiatica, gotu kola, Asiatic pennywort, neuroprotection,
and memory” through the electronic databases including Sciencedirect, Web of Science, Scopus, Pubmed, and Google Scholar.
According to the literature survey, C. asiatica (gotu kola) has been reported to have a comprehensive neuroprotection by
different modes of action such as enzyme inhibition, prevention of amyloid plaque formation in Alzheimer’s disease, dopamine
neurotoxicity in Parkinson’s disease, and decreasing oxidative stress. Therefore, C. asiatica could be suggested to be a desired
phytopharmaceutical with neuroprotective effect emerged from traditional medicine.
1. Introduction
Centella asiatica (L.) Urban (Syn.Centella coriacea Nannfd.,
Hydrocotyle asiatica L., Hydrocotyle lunata Lam., and Tri san-
thus cochinchinensis Lour.) is a tropical medicinal plant from
Apiaceae family native to Southeast Asian countries such
as India, Sri Lanka, China, Indonesia, and Malaysia as well
as South Africa and Madagascar [1]. C. asiatica, commonly
known as “Gotu kola, Asiatic pennywort, Indian pennywort,
Indian water navelwort, wild violet, and tiger herb” in Eng-
lish, is a tropical plant, which has been also cultivated suc-
cessfully due to its medical importance in some countries
including Turkey, and it has a long history of utilization in
ayurvedic and Chinese traditional medicines since centuries
[2]. The leaves, which are edible, are in yellowish-green color,
thin, alternate with long petioles, and quite characteristic
reniform, orbicular, or oblong-elliptic shapes with seven
veins [3](Figure 1). The plant grows horizontally through
its green to red stolones which combine to each other and
roots in underground. Monographs of the plant describing
mainly its wound healing and memory enhancement effects
exist in the European Pharmacopeia, Commission E of the
German Ministry of Health, and World Health Organization
(WHO) [4]. In addition to neuroprotective effect of C. asi-
atica, it has been reported to own a wide range of biological
activities desired for human health such as wound healing
[5–7], anti-inflammatory [8,9], antipsoriatic [10], antiulcer
[11,12], hepatoprotective [13], anticonvulsant [14], sedative
[15], immunostimulant [16], cardioprotective [17,18],
antidiabetic [19], cytotoxic and antitumor [20,21], antiviral
[22], antibacterial [23], insecticidal [24], antifungal [25],
antioxidant [26–28], and for lepra [29] and venous defi-
ciency treatments [30,31].
Numerous preparations of this plant in various phar-
maceutical forms recommended for several indications in-
cluding neurological disorders are available allover the world.
Taking this fact into consideration, many researchers have
focused on neuroprotective effect of C. asiatica in order
to confirm its traditional use on scientific base. For this
purpose, a literature survey has been performed using the
databases searched up to the year 2012 for the latest
information on C. asiatica. This paper aims to cover up
2 Evidence-Based Complementary and Alternative Medicine
Figure 1: Centella asiatica (L.) Urban (Apiaceae).
HO
HO
O
OH
OH
OH
R2
R2
R1
R1
OR3
R3
HH
H
H
H
CH2OH
CH2OH
CH2OH
CH2OH
CH3
Asiatic acid
Madecassic acid
Madasiatic acid
Asiaticoside
Madecassoside
Glucose-glucose-rhamnose
Glucose-glucose-rhamnose
Figure 2: The major triterpene saponoside derivatives found in
Centella asiatica.
in vitro,in vivo, and clinical studies reporting the results rele-
vant to neuroprotective effect of this plant.
2. Phytochemical Content of
C. asiatica
C. asiatica has been reported to contain a vast number
of compounds belonging to different chemical classes. The
major chemical class found in this plant is triterpene sapono-
sides. The major ones are known as asiatic acid, madecassic
acid (6-hydroxy-asiatic acid), asiaticoside, madecassoside,
and madasiatic acid (Figure 2), betulinic acid, thankunic
acid, and isothankunic acid [32,33]. Moreover, There are
some other triterpenes such as brahmic acid, centellin,
centellicin, asiaticin, bayogenin, terminolic acid, 3β,6β,23-
trihydroxyolean-12-en-28-oic acid, 3β,6β,23-trihydroxyurs-
12-en-28-oic acid, 3-O-[α-L-arabinofuranosyl] 2α,3β,6β,23-
αtetrahydroxyurs-12-en-28-oic acid, centellasapogenol A,
HO O
O
O
O
OH
OH
OH
Figure 3: Castilliferol.
HO
HO
HO
O
O
O
O
OH
OH
OH
COOH
Figure 4: Isochlorogenic acid.
centellasaponins A-D, ursolic acid, pomolic acid, 3-epimas-
linic acid, 23-O-acetylmadecassoside, and 23-O-acetylasiat-
icoside B [34–41].
Presence of several flavonoid derivatives such as quer-
cetin, kaempferol, patuletin, rutin, apigenin, castilliferol
(Figure 3), castillicetin, and myricetin has been reported in
C. asiatica [35,39,42], while isolation of polysaccharides
(e.g., centellose) [43], polyacetylenes (e.g., cadinol, acetox-
ycentellinol, centellin, centellicin, and asiaticin) [36,44],
sterols (e.g., 11-oxoheneicosanil-cyclohexane, dotriacont-8-
en-1-oic acid, sitosterol 3-O-β-glucoside, stigmasterol 3-O-
β-glucoside, and castasterone) [41,45,46], and phenolic
acids (e.g., rosmarinic acid, 3,5-di-O-caffeoil quinic acid, 1,
5-di-O-caffeoil quinic acid, 3,4-di-O-caffeoil quinic acid, 4,
5-di-O-caffeoil quinic acid, ettacrynic acid, chlorogenic acid,
and isochlorogenic acid [Figure 4]) [40,42,47]hasbeen
also identified in this species. In our quantitative study on C.
asiatica of Turkish origin by HPLC, we reported existence of
several phenolic acids, for example, p-hydroxybenzoic acid,
vanillic acid, p-coumaric acid, o-coumaric acid, and trans-
cinnamic acid [48].
On the other hand, only a few studies have described
the chemical composition of the essential oils obtained from
C. asiatica from Japan, South Africa, and Thailand, which
mainly consisted of monoterpene and sesquiterpene deriva-
tives [49–51]. In our work, we examined the essential oil
composition of C. asiatica cultivated in Turkey by GC-MS
for the first time and identified α-copaene as the major
component [48].
3. Neuroprotective Activity of
C. asiatica
3.1. In Vitro Studies. C. asiatica (gotu kola) is a reputed
plant species for its traditional use in ayurvedic and Chinese
medicines [52], and its positive effects on brain aging have
been generally attributed to its two major triterpene sapono-
sides; asiatic and madecassic acids as well as their heterosides;
asiaticoside and madecassoside, respectively. For instance,
Evidence-Based Complementary and Alternative Medicine 3
the hydroalcoholic extract of the plant was tested in vitro
against acetylcholinesterase (AChE), the key enzyme taking a
critical role in the pathogenesis of Alzheimers disease (AD).
Since deficit in the level of acetylcholine (ACh), which is
hydrolyzed by AChE, has been identified in the brains of
AD patients, inhibition of AChE as well as its sister enzyme
butyrylcholinesterase (BChE) has become a rational target in
drug development against AD [53]. The extract was found
to inhibit AChE with 50% of inhibition rate at 150 μg/mL
concentration by the spectrophotometric method of Ellman
[54]. In our study on the ethanol extracts prepared from the
aerial parts of C. asiatica of both Turkish and Indian origins
along with the standardized gotu kola extract (containing
10.78% of total asiaticoside and madecassoside) imported
from China, we comparatively examined inhibitory potential
of these three extracts against AChE, BChE, and tyrosinase
(TYRO) at 50, 100, and 200 μg/mL concentrations [48].
As aforementioned that cholinesterases are the important
enzymes for AD treatment, TYRO has become an important
target for Parkinson’s disease (PD) since this enzyme plays
a role in neuromelanin formation in the human brain and
could be significant in occurrence of dopamine neurotoxi-
city associated with neurodegeneration linked to PD [55].
According to our results obtained at 200 μg/mL, only the
standardized extract was found to inhibit AChE (48.28 ±
1.64%), whereas the ethanol extracts of the plant samples
from Turkey and India exerted 46.95 ±0.94% and 70.30 ±
3.77% against BChE, respectively, and a notable inhibition
against TYRO (42.83 ±4.21% and 56.20 ±3.17%, resp.).
Awad et al. investigated inhibitory property of C. asiatica
extract towards glutamic acid decarboxylase (GAD) and γ-
aminobutyric acid transaminase (GABA-T), which are the
enzymes responsible for GABA metabolism and found out
that the extract stimulated the activity of GAD over 40%
[56]. On the other hand, the leaf extract of C. asiatica grow-
ing in China was shown to display neuroprotection through
enhancing phosphorylation of cyclic AMP response element
binding protein (CREB) in neuroblastoma cells in Aβ(1–
42) proteins found within the amyloid plaques occurring in
the brains of AD patients [57]. In another study [58], effect
of the aqueous leaf extract of the plant on monomers or
oligomers that lead to formation of Aβ(1–42) proteins in
AD via aggregation was examined using both thioflavin-T
test and transmission electron microscope; however, it was
observed not to cause any inhibition on aggregation of the
monomers and oligomers. Inhibitory activity of the aqueous
extract of C. asiatica that contained 84% of asiaticoside was
tested by the radioenzymatic assay against phospholipase
A2(PLA2), which play role in neuropsychiatric diseases.
The findings pointed out to the fact that the extract could
inhibit Ca2+-independent PLA2and cytosolic PLA2[59].
The ethanol extract of the plant was observed to cause an
increase in neurite development in human SH-SY5Y cell
lines at 100 μg/mL concentration, whereas its aqueous extract
did not lead any increase in the same cells [60]. Then, the
subfractions of the ethanol extract were also tested further
in the same assay for neuritic development, and the most
effective subfraction was demonstrated to have a nonpolar
chemical nature. According to the results of that study, the
authors concluded that C. asiatica extract might be beneficial
in prevention of neuronal damage.
Lee et al. studied neuroprotective potential of thirty six
derivatives of asiatic acid prepared by various structural
modifications and tested in primary cell culture consisting of
rat cortical neurons exposed to glutamate, which is known
as a neurotoxin [61]. Three of the compounds displayed
higher protective activity than asiatic acid per se and also
significantly reduced production of glutamate-induced nitric
oxide (NO) as well as levels of glutathione, glutathione
peroxidase, and some other related enzymes.
3.2. In Vivo Studies. Neuroprotective effect of C. asiatica and
its major triterpene saponosides has been extensively studied
through different experimental models on animals such as
passive avoidance and elevated-plus labyrinth tests for mem-
ory enhancing effect [62]. A research was carried out in rats
to determine effect of the aqueous extract of C. asiatica on
intracerebrovascular streptozocin-induced memory associ-
ated with sporadic type of AD by applying the extract at
doses of 100, 200, and 300 mg/kg (b.w.) and measuring some
oxidative stress parameters such as glutathione, superoxide
dismutase (SOD), and catalase (CAT) [63]. While a clear
dose-dependent improvement was observed in memory-
related behaviors in the rat group administered the extract at
200 mg/kg (b.w.) dose, a serious decrease in malondialdehyde
(MDA) and an increase in glutathione and CAT levels were
recorded, which led to a final suggestion by the authors that
C. asiatica extract has a positive effect on memory that is
also related to its remarkable antioxidant effect. The same
research group subjected this extract to passive avoidance
and spontaneous locomotor activity behavioral tests using
pentylenetetrazole-(PTZ-) induced memory loss in rats at
100 and 300 mg/kg (b.w.) doses [64]. Following the behav-
ioral tests, MDA and glutathione levels were determined in
the rat brains as oxidative stress markers, which significantly
contribute to neurodegeneration. Accordingly, the extracts
at the tested doses caused a notable improvement in all test
parameters.
In another study by Rao et al. [65], enhancing effect of
C. asiatica extract on learning and memory was examined
during 15 days at 200, 500, 700, and 1000 mg/kg (b.w.)
doses by oral administration to mice. Open area, light/dark
compartment, and radial-armed labyrinth tests were applied
as experimental models, while AChE activity and dendritic
arborization development were taken into consideration as
biochemical markers. According to the findings, the extract
displayed improving effect in radial-armed labyrinth test,
whereas it did not cause any change in locomotor activity. On
the other hand, extract administration resulted in an increase
in AChE activity and dendritic arborization in CA3 neurons
located in hippocampus. Thus, the authors concluded that
the extracts may positively influence neuronal morphology,
especially in young adult mice. In a similar study performed
by the same researchers, the fresh leaf extract of C. asiatica
was given to adult mice at 2, 4, and 6 mL/kg doses during
2, 4, and 6 weeks, respectively [66]. After these periods, the
removed brains of mice were investigated under microscope,
4 Evidence-Based Complementary and Alternative Medicine
which pointed out to the evidence that the extract given
at 6 mL/kg dose during 6 weeks caused a significant aug-
ment in dendritic arborization in neurons. These authors
came to another similar conclusion that the juice obtained
by pressing the fresh leaves of C. asiatica tested in the
same experimental model in mice also enhanced dendritic
arborization [67]. Besides, C. asiatica extract was shown to
reduce levels of β-amyloid plaques in hippocampus in mice
[68].
Shinomol and Muralidhara investigated effect of C. asi-
atica extract against oxidative stress and mitochondrial dys-
function induced by 3-nitropropionic acid, a fungal-derived
neurotoxin, in the brains of male prepubertal mice, and the
extract was found to diminish oxidative stress remarkably
through influencing the parameters such as MDA and rad-
ical oxygen species [69]. In a related study on rats, C.
asiatica extract was reported to have a protective effect
against mitochondrial damage occurred in PD by means of
improving oxidative stress parameters [70]. Anticonvulsant
effect of the crude material and extracts prepared from C.
asiatica, also known as “brahmi” in Hindu, was determined
in PTZ-induced convulsion model in rats and compared
with fenitoin as the reference drug [71]. The data indicated
that the crude material of the plant exerted a mild level of
anticonvulsant effect at 500 mg/kg dose, while the methanol
extract had superior effect to that of the crude material at
3rd and 6th hs. The extract prepared with propylene glycol
also produced a dose-dependent anticonvulsant activity at
500 and 1000 mg/kg (b.w.) doses. Similarly, Ganachari et al.
demonstrated in vivo anticonvulsant effect of the hydroal-
coholic extract of C. asiatica against PTZ- and strychnine-
induced opistotonus convulsions at 100 mg/kg (b.w.) [72].
Moreover, the extract was observed to reduce lipid per-
oxidation and spontaneous locomotor activity, whilst it
potentiated pentobarbital-induced sleeping duration and
diazepam-induced hyperactivity. In another paper [73], the
ethyl acetate fraction of C. asiatica as well as combination of
the fraction with some antiepileptic drugs including fenitoin,
valproate, and gabapentin individually was administered
intraperitoneally to the mice with convulsion induced by
PTZ and found that the combinations caused an additive
effect producing a higher anticonvulsant activity than each
of the drugs. Additionally, neurotoxicity of the fraction
and each combination was established by rotarod test,
and combination of the extract with gabapentin was less
neurotoxic. In the light of this evidence, the authors stated
that conjoint use of the ethyl acetate fraction of C. asiatica
with epileptic drugs might be beneficial for epileptic patients.
In another study [74], De Lucia et al. reported anticonvulsant
and sedative activities of the hydroalcoholic extract of C.
asiatica in rats using elevated-plus labyrinth and PTZ-
induced convulsion models, and the extract was also shown
to exert low toxicity by chronic application with the LD50
value of 675 mg/kg (b.w.). Anticonvulsant activity of the
hexane, chloroform, ethyl acetate, water, and n-butanol ex-
tracts prepared from C. asiatica was determined using PTZ-
induced convulsion model in male Wistar rats, and effect of
the extracts was also searched on Na+/K+,Mg
2+,andCa
2+-
ATPase activity [75]. The results pointed out to an increase in
activity of three types of ATPases in the extract-administered
groups accompanied by anticonvulsant activity. Anxiolytic
activity of the hexane, ethyl acetate, and methanol extracts
of C. asiatica and asiaticoside was tested using elevated-plus
labyrinth, open area, social interaction, locomotor activity,
and new cage models in rats [76]. The results indicated
that only the methanol and ethyl acetate extracts of the
plant along with asiaticoside displayed anxiolytic activity in
elevated-plus labyrinth test. In another paper [77], sedative
effect of C. asiatica was mainly attributed to brahmoside and
brahminoside, the triterpene derivatives, whereas anxiolytic
activity was suggested to be partly resulted from the inter-
action with cholecystokinin receptors (CCKB),agroupof
G protein-coupled receptors which are considered to take a
potential place in modulation of anxiety, nociception, and
memory.
C. asiatica extract was administered orally to old rats
during 60 days at 300 mg/kg (b.w.) dose per day, and the
cortex, hypothalamus, striatum, cerebellum, and hippocam-
pus regions of the rat brains were investigated in terms
of lipid peroxidation and protein carbonyl (PCO) contents
[78]. The researchers made a statement that the extract
may be showing a neuroprotective effect in old rats by way
of bringing about a significant decrease in PCO contents
and lipid peroxidation. Radical scavenging effect of the
chloroform-methanol (4 : 1) extract of the plant was exam-
ined in monosodium glutamate-treated Sprague-Dawley
female rats at 100 and 200 mg/kg doses [79]. Following the
extract administration, a significant increase was observed
in SOD and CAT levels, whereas glutathione level was not
influenced. Flora and Gupta reported that the flavonoid
fraction of C. asiatica demonstrated a protecting effect
against lead acetate-induced neurotoxicity in mice through
antioxidant mechanisms [80]. In another paper, asiatic acid,
one of the major triterpene derivatives in C. asiatica,ad-
ministered orally at 30, 75, and 165 mg/kg (b.w.) doses,
was shown to have neuroprotective property in mice with
permanent cerebral ischemia by evaluating infarct volume
and behavioral changes between 1st and 7th days [81]. In
the same study, the compound was additionally investigated
in HT-22 cells exposed to oxygen glucose in terms of cell
viability and mitochondrial membrane potential. Asiatic acid
considerably diminished the infarct volume by 60% and
26% at the 1st and 7th days, respectively, which improved
neurological status at 24 h after ischemia. The authors con-
cluded that asiatic acid, which might be mediated to some
extent by decreasing blood-brain barrier permeability as well
as reduction in mitochondrial damage, could be useful for
cerebral ischemia treatment.
Probable improving effect of C. asiatica extractat150
and 300 mg/kg (p.o.) doses was assessed against colchicine-
induced memory using Morris water maze and plus-maze
performance tests in male Wistar rats as well as oxidative
damage parameters such as lipid peroxidation, nitrite, re-
duced glutathione, glutathione-S-transferase, SOD, and as
a biochemical parameter, AChE activity [82]. The 25-day
chronic administration of the extract caused a significant
improvement in memory and oxidative damage parameters
along with AChE activity. On the other hand, asiaticoside
Evidence-Based Complementary and Alternative Medicine 5
from C. asiatica exerted a neuroprotective effect against PD
by reversing neurotoxicity induced by 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP) in rats via balancing
dopamine and antioxidant mechanism [83].
Antidepressant activity of C. asiatica was evaluated using
its triterpene fraction in cortex, hippocampus, and thalamus
regions of rat brains by determining the corticosterone lev-
els [84]. The triterpene fraction created a momentous dim-
inution in corticosterone level and a notable increase in
amount of monoamine-related neurotransmitters.
3.3. Clinical Studies. Although many in vivo studies have
been carried out on central-nervous-system-(CNS-) related
effects of C. asiatica, the literature survey has revealed
presence of only a limited number of clinical studies with this
species. The results of an early double-blind clinical study
on the children with mental deficiency in 1977 showed that
a statistically significant improvement was recorded in the
children in 3rd and 6th months following administration of
C. asiatica [85].
Possible effect of the capsulated aqueous extract of
C. asiatica standardized to contain 29.9 mg/g tannic acid,
1.09 mg/g asiaticoside, and 48.89 mg/g asiatic acid was de-
termined in a randomized, double-blind, and placebo-con-
trolled clinical study carried out on 28 healthy and elder
volunteers consisting of 4 men and 24 women with the
average age of 65.05 ±3.56 in Thailand [86]. The extract
was given to the subjects once a day at 250, 500, and 750 mg
doses during 2 months, and their cognitive performance
was evaluated by a variety of parameters using computer-
assisted techniques. The findings revealed that the highest
dose of C. asiatica extract tested in this study possessed a
cognitive enhancing effect. In a similar study [87], Dev et
al. investigated effect of the capsulated C. asiatica extract
on cognitive performance conducted with a total 41 of
middle-age healthy subjects consisting of 22 women and
19 men. The extract was given to the subjects in a capsule
once a day during 2 months. The cognitive performance
was measured using Woodcock-Johnson Cognitive Abilities
Test III (WJCAT III), and the extract was found to have
a remarkably positive influence on all of the subjects. A
recent clinical study consisting of 60 elderly subjects with
average age of 65 with mild cognitive deficiency indicated
that C. asiatica extract administered at 500 mg dose twice
per day during 6 months led to a significant cognitive
improvement according to Mini Mental State Examination
(MMSE) scoring [88].
4. Precautions
Although C. asiatica is one of the top-selling herbal medi-
cines due to its remarkable pharmacological effects, some
precautions should be taken for this plant. It has been known
to be safe when taken at the recommended doses; however,
skin irritation and contact dermatitis have been reported
in some cases [89–91]. In a very early paper in 1969 [92],
the total saponoside fraction containing brahmic acid and
its derivatives of the plant was stated to cause infertility
in an experiment conducted on human and rat sperms. In
consistency with this paper, Newall et al. also affirmed that
infertility was observed in female mice after oral admin-
istration of C. asiatica [93].Anotherresultpointedoutto
the fact that chronic treatment of C. asiatica might induce
a spontaneous abortion in pregnant women [94]. Since the
plant may bring about a raise in blood sugar and lipid
levels, diabetic and hyperlipidemic patients should consider
taking preparations of C. asiatica [93]. Briefly, maximum
duration suggested for the use of C. asiatica preparations is
6 weeks, and at least, a 2-week break is needed after every
long duration use. Even though no drug interaction has
been reported for this plant up to date, pregnant and breast-
feeding women are suggested to avoid using this herbal
medicine.
5. Conclusion
C. asiatica, widely known as “gotu kola,” is a reputed me-
dicinal plant for its various pharmacological effects favorable
for human health. Besides its potent wound healing property,
a number of studies described the noteworthy protective
effect of the plant against several diseases of CNS. Biological
effects of C. asiatica have been generally attributed to the
major triterpene derivatives including asiatic acid, made-
cassic acid, asiaticoside, madecassoside, and brahmic acid.
The neuroprotective effect of the plant has been suggested
to result from different mechanisms, most of which have
referred to positive influences on oxidative stress parameters.
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