Centella asiatica in Dermatology: An Overview

Abstract

Centella asiatica is a medicinal plant that was already used as a 'panacea' 3000 years ago. The active compounds include pentacyclic triterpenes, mainly asiaticoside, madecasosside, asiatic acid and madecassic acid. We have conducted an overview to summarize current knowledge on the results of scientific in vitro and in vivo experiments focused on the improvement of the healing process of small wounds, hypertrophic scars and burns by C. asiatica. In this paper, we discuss the data on constituents, recommended preparations and the potential side effects of C. asiatica. Copyright © 2014 John Wiley & Sons, Ltd.

Full text

REVIEW
Centella asiatica in Dermatology: An Overview
Wiesława Bylka,
1
*Paulina Znajdek-Awiżeń,
1
Elżbieta Studzińska-Sroka,
1
Aleksandra Dańczak-Pazdrowska
2
and Małgorzata Brzezińska
1
1
Department of Pharmacognosy, Poznan University of Medical Sciences, Święcickiego 4, 60-781 Poznań, Poland
2
Department of Dermatology, Poznan University of Medical Sciences, Przybyszewskiego 49, 60-355 Poznan, Poland
Centella asiatica is a medicinal plant that was already used as a ‘panacea’3000 years ago. The active compounds
include pentacyclic triterpenes, mainly asiaticoside, madecasosside, asiatic acid and madecassic acid. We have
conducted an overview to summarize current knowledge on the results of scientific in vitro and in vivo
experiments focused on the improvement of the healing process of small wounds, hypertrophic scars and burns
by C. asiatica. In this paper, we discuss the data on constituents, recommended preparations and the potential
side effects of C. asiatica. Copyright © 2014 John Wiley & Sons, Ltd.
Keywords: Centella asiatica; triterpenes; review; dermatology.
INTRODUCTION
Some of herbal remedies may be particularly helpful in
treating and relieving symptoms of skin diseases, due
to the presence of various compounds responsible for
their activity.
One of the plants used in dermatology is Centella
asiatica (L.) Urban., synonym Hydrocotyle asiatica L.
from the family Apiaceae, also known by the common
name Gotu kola or Indian pennywort. It grows in the
tropical regions of Asia, Oceania, Africa and America.
C. asiatica herb is recommended in the treatment
of dermatoses and skin lesions such as excoriations,
burns, hypertrophic scars or eczema as well as in non-
dermatological diseases like gastric ulcers, gastric
mucosal lesions (Shinomol and Muralidhara, 2011),
anxiety (Wijeweeraa et al., 2006) and for improving cog-
nition in neurodegenerative disorders (Subathra et al.,
2005). C. asiatica has also been found beneficial in
chronic venous insufficiency, mainly by improvement
of microcirculation (Chong and Aziz, 2013). C. asiatica
extract (International Nomenclature of Cosmetic Ingre-
dients, INCI) is used also as an ingredient of cosmetics
(Bylka et al., 2013).
Many studies present activity of C. asiatica, but until
now there have been no reviews presenting the scientific
information about the usage of H. asiatica in dermato-
logical diseases. For this reason, this study provides an
overview of the current knowledge on the in vitro and
in vivo experiments, focused on the activity of C. asiatica
extracts and individual compounds in facilitating the
process of healing wounds, psoriasis and scleroderma
lesions. The mechanisms of the above-mentioned activ-
ities as well as the potential side effects are discussed.
METHODS
The following electronic English databases were
searched: Ovid Medline, Pubmed and The Cochrane
Library, from 1988 up to March 2013. They have been
searched by the title and abstract using the following
search terms: Centella asiatica,Hydrocotyle asiatica,
Gotu kola, Indian pennywort, centelloids, asiaticoside,
madecasosside, asiatic acid, madecassic acid, wounds,
wound healing, burn wounds, scleroderma, psoriasis
and toxicity. Hand searches were also conducted for
publications not stored in the databases (e.g. webpages).
Reference lists of all articles were searched for further
publications.
For the selection of the manuscripts, three indepen-
dent investigators (PZA, ESS and MB) assessed at first
all the titles and abstracts and then through the full-text
analysis of the publications, against pre-defined inclu-
sion criteria. Disagreements over a study’s inclusion
were resolved by discussion between them and the con-
sensus, arbitrated by authors WB and ADP.
CHEMICAL CONSTITUENTS
Ursane type pentacyclic triterpenoids known as centelloids,
mainly: asiaticoside, madecasosside (brahminoside), asiatic
acid and madecassic acid (brahmic acid) (Fig. 1) were the
most important constituents isolated from C. asiatica.Other
triterpenoids in Gotu kola include: asiaticoside C, D, E, F;
centellasaponin B, C; isothankunic acid and oleanane type
saponins, e.g. terminolic acid; centellasaponin D. C. asiatica
contains about 0.1% essential oils with α-humulene,
germacrene B/D, β-caryphyllene, flavonoids, sesquiter-
penes, steroids (Brinkhaus et al., 2000; James and Duebery,
2009; James and Dubery, 2011; Nhiem et al., 2011). Sapo-
nins may account for 1% to 8%, according to the European
Pharmacopoeia, not less than 6.0% (Ph.Eur. 2011).
* Correspondence to: Wiesława Bylka, Department of Pharmacognosy,
Poznan University of Medical Sciences, 60-781 Poznań,Święcickiego 4, Poland.
E-mail: wieslawabylka@tlen.pl
PHYTOTHERAPY RESEARCH
Phytother. Res. 28: 1117–1124 (2014)
Published online 7 January 2014 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/ptr.5110
Copyright © 2014 John Wiley & Sons, Ltd.
Received 05 June 2013
Revised 29 November 2013
Accepted 03 December 2013

HERBAL PREPARATIONS
Pharmacological and clinical studies were carried out on
the defined extracts as well as undefined aqueous or alco-
hol extracts (Table 1). However, information on the
medicinal products suggests that all extracts: titrated ex-
tract of C. asiatica (TECA), total triterpenoid fraction of
C. asiatica (TTFCA), total triterpenic fraction (TTF), as
well as C. asiatica total triterpenic fraction (CATTF) and
estratto titolato di C. asiatica (ETCA) are different acro-
nyms of the same extract, contained in the used prepara-
tions: Madecassol®, Centellase® or Blastoestimulina®.
These extracts include 40% of asiaticoside and a 60%
mixture of asiatic and madecassic acids (Brinkhaus et al.,
2000; EMEA (European Medicines Agency), 2012).
One to two tablets (10 mg/tabl.) three times a day for
adults and a half of this dose for children under 3 years
of age are recommended by the European Medicines
Agency (EMEA) in the case of non-healing wounds, hy-
pertrophic scars or keloids in the active phase. For external
use, to support the local treatment and to improve the
granulation phase of non-healing ulcers and wounds, 1%
cream is recommended. Disinfection of the wound/ulcer
is required before treatment with TTFCA. Moreover, 1%
ointment and 2% powder are available for the treatment
of non-healing wounds. Two to three applications of
ointment and 1–3 of powder per day are recommended.
The ointment may also be used to cover skin on radiother-
apy (EMEA, 2012).
RESULTS
This review identified 31 studies on facilitating the
process of healing wounds, psoriasis and scleroderma
lesions by C. asiatica extracts and its individual com-
pounds such as: asiaticoside, madecassoside, asiatic acid
and madecassic acid. Studies include 19 in vitro, ten
in vivo and two clinical studies with different methodol-
ogies and importance. Twenty three citations were pub-
lished after 2000, eight between 1988 and 2000. Results
from the included studies are presented below and also
summarized in chronological order in Table 2.
In vitro experiments
Wound healing. Wound healing is a complex biological
process involving coagulation, inflammation, cytokine
production, cell migration, proliferation and differentia-
tion, angiogenesis, synthesis and remodeling of extracel-
lular matrix (including collagen production and
deposition). Type I and III collagen are the major com-
ponents of the skin extracellular matrix. Both types play
an important role in the wound healing process. As a
result, proliferation of epithelial cells and wound con-
traction occur (Lu et al., 2004a, 2004b; Liu et al., 2008).
C. asiatica extracts, individual triterpene compounds
and the mixture of triterpenoids from C. asiatica have
been proven to support wound healing in a large num-
ber of scientific reports.
A statistically significant increase in the percentage of
collagen and cell layer fibronectin in cultures of human
skin fibroblasts, after application of TTFCA extract
(25 μg/mL), was detected (Tenni et al., 1988).
The TECA and its components including asiatic acid,
madecassic acid and asiaticoside have been studied on
human foreskin fibroblast monolayer cultures. TECA
increased the collagen synthesis in a dose-dependent
manner. In addition, TECA and all terpenes increased
the intracellular free proline level, but this effect was
independent of the stimulation of collagen synthesis
(Maquart et al., 1990).
The influence of asiatic acid, madecassic acid and
asiaticoside on human skin fibroblast type I collagen syn-
thesis was investigated in vitro separately for each agent
and in combination. Additionally, the culture was or was
not stimulated with ascorbic acid. In the presence of
ascorbic acid, secretion of type I collagen was higher for
each individual component and for the mixture, than in
the absence of ascorbic acid (Bonté et al., 1994).
To determine secretion of type I and III collagen in
human fibroblast culture with or without stimulation
with asiaticoside and madecassoside, the enzyme-linked
immunosorbent assay (ELISA) was performed. The
secretion of type I collagen was increased for 25–30%
with asiaticoside and madecassoside. Authors concluded
that C. asiatica extracts may facilitate maturity of a scar
by increasing the amount of type I collagen and thus in-
creasing the type I:III collagen ratio (Bonté et al., 1995).
The activity of C. asiatica triterpenes (asiatic acid,
madecassic acid asiaticoside and madecassoside) and
Figure 1. Triterpenes in Centella asiatica.
Asiatic acid R=CH
3
;R
1
=H; R
2
=COOH
Asiaticoside R=CH
3
;R
1
=H; R
2
=COO-glc(1→6)glc(1→4)rha
Madecassic acid R=CH
3
;R
1
=OH; R
2
=COOH
Madecassoside R=CH
3
;R
1
=OH; R
2
=COO-glc(1→6)glc(1→4)rha
Table 1. Investigated extracts of C. asiatica
Extract Composition of extract
TECA Asiatic acid (30%), madecassic
acid (29–30%), asiaticoside (40%)Titrated extract of
C. asiatica
TTFCA Asiatic acid (30%), madecassic
acid (30%), asiaticoside (40%)Total triterpenoid fraction
of C. asiatica
TTF Asiatic acid and madecassic
acid (60%), asiaticoside (40%)Total triterpenic fraction
CATTF Undefined
C. asiatica total triterpenic
fraction
ETCA Undefined
Estratto titolato di
C. asiatica
1118 W. BYLKA ET AL.
Copyright © 2014 John Wiley & Sons, Ltd. Phytother. Res. 28: 1117–1124 (2014)

Table 2. Studies of the extracts and constituents of C. asiatica in chronological order
Extract/compound Model/effect/route of application
a
Reference
IN VITRO MODELS
WOUND HEALING
TTFCA Human skin fibroblast/↑collagen and fibronectin synthesis Tenni et al., 1988
TECA, asiatic acid, madecassic
acid and asiaticoside
Human foreskin fibroblast monolayer cultures/↑proline level,
collagen synthesis
Maquart et al., 1990
Asiatic acid, madecassic acid,
asiaticoside
Human skin fibroblast, stimulated or not stimulated with
ascorbic acid/↑type I collagen synthesis
Bonté et al., 1994
Asiaticoside, madecassoside Human fibroblast culture/↑type I and III collagen synthesis Bonté et al., 1995
TECA, asiatic acid, madecassic
acid asiaticoside and
madecassoside
Human fibroblasts, DNA microarrays analysis/changes of
genes expression involved in angiogenesis and wound healing
Coldren et al., 2003
Asiaticoside Human dermal fibroblasts, DNA microarray analysis/changes
of genes expression responsible for cell proliferation, cell cycle,
extracellular matrix
Lu et al., 2004a, 2004b
Asiaticoside Human dermal fibroblasts/↑type I collagen synthesis,
activation of Smad pathway
Lee et al., 2006
Ethanolic extract Human fibroblast cells/↑collagen synthesis Hashim et al., 2011
Methanolic extract, six
triterpenoid compounds
LPS-stimulated RAW 264.7 cells/↓NO production, TNF-αsecretion Nhiem et al., 2011
Asiaticoside Keloid-derived fibroblasts/↑collagen synthesis, normalization
of healing process
Tang et al., 2011
Asiaticoside Human skin fibroblasts/↑migration and proliferation of the
fibroblasts, ↑ECM synthesis
Lee et al., 2012
Aqueous extract Rabbit corneal epithelial cells wound healing model/↑cell migration,
changes of proliferation and cell cycle
Ruszymah et al., 2012
Asiaticoside Human periodontal ligament cells/↑mRNA and proteins of
fibronectin and type I collagen,↓metalloproteinase-I
mRNA expression
Nowwarote et al., 2013
ANTIMICROBIAL ACTIVITY
Hexane, carbon tetrachloride,
chloroform fractions from
methanolic extract
Disc diffusion method/Antimicrobial activity Ullah et al., 2009
ANTIOXIDANT ACTIVITY
Ethanolic extract Human dermal fibroblasts/↑collagen synthesis Hashim et al., 2011
DPPH assay/antioxidant effect
ANTI-PSORIATIC ACTIVITY
Water extracts, asiaticoside,
madecasosside
SVK-14 keratinocytes/Inhibition of growth of SVK-14
keratinocytes
Sampson et al., 2001
IN VIVO MODELS
WOUND HEALING
Ointment, cream, gel with 1%
of aqueous extract
Wounds/↑cellular proliferation, collagen synthesis, tensile
strength/topical application in rats
Sunilkumar et al., 1998
Asiaticoside (0.2% solution) Wounds/↑levels of enzymatic and non- enzymatic antioxidants/
topical application in rats
Shukla et al.,
1999a, 1999b
Asiaticoside (0.2% solution) Normal and delayed wound, hydroxyproline content and tensile
strength/topical and oral application in guinea pigs
Shukla et al., 1999a
TECA, asiatic acid, madecassic
acid and asiaticoside
Wound chamber model implanted under the skin of rats/↑dry weight,
DNA, protein, hydroxyproline, collagen synthesis/injections
Maquart et al., 1999
Asiatic and madecassic
acids (mixture)
Influence on the connective tissue of rats/↑collagen synthesis,
tensile strength, ↓scar tissue/oral or subcutaneous administration in rats
Brinkhaus et al., 2000
Ethanolic extract Normal and dexamethasone suppressed wound/↑wound healing
(epithelization, contraction, tensile strength)/topical application in rats
Shetty et al., 2006
Madecassoside Burn wound, ↑antioxidative activity, collagen synthesis, angiogenesis/
oral administration in mice
Liu et al., 2008
Asiaticoside Burn wound/influence on the level of cytokines, ↑angiogenesis,
stimulation VEGF production, MCP-1, IL-1/topical application on
the backs of mice
Kimura et al., 2008
(Continues)
1119THE EXPERIMENTS ABOUT USE OF CENTELLA ASIATICA IN DERMATOLOGY
Copyright © 2014 John Wiley & Sons, Ltd. Phytother. Res. 28: 1117–1124 (2014)

TECA depends on the modulation of the expression of
genes involved in angiogenesis and wound healing.
TECA was demonstrated to carry out changes in
hyaladherin and cytokine expression, which may cause
a decrease of proteolysis in the extracellular matrix,
and therefore support the accumulation of collagen
and fibronectin. Proangiogenic changes in the expres-
sion of a number of growth factors were detected
(Coldren et al., 2003).
Asiaticoside influences the wound healing even in
infected wounds. The in vitro studies by Lu et al.
(2004a, 2004b) on human dermal fibroblasts with
DNA microarray analysis proved that in the presence
of asiaticoside (30 μg/mL) changes of the genes expres-
sion are observed. These genes were responsible for cell
proliferation, cell cycle process and extracellular matrix
synthesis. Furthermore, type I and type III procollagen
mRNA level and proteins level increased in response
to asiaticoside.
Lee et al. (2006) have shown that asiaticoside signifi-
cantly induced type I collagen synthesis in human der-
mal fibroblast. Type I collagen synthesis is stimulated
by transforming growth factor β(TGF-β). The Smad
proteins transmit the signal downstream from the
TGF-βreceptor into the nucleus. Following the binding
of TGF-βto its receptors, the receptor-regulated Smads
(so called R-Smads, which include Smad 1, 2, 3, 5 and 8)
are phosphorylated and then translocated to the nu-
cleus, where they act as regulators of the target genes
expression, e.g. type I collagen gene. Asiaticoside in-
duced phosphorylation of Smad2 and Smad3. Interac-
tions between Smad3 and Smad4 after stimulation with
asiaticoside were also observed. It was proved that
asiaticoside induced translocation of Smad3–Smad4
complex into the nucleus. Moreover, Smad2 phosphory-
lation and synthesis of type I collagen induced by
asiaticoside were not inhibited by SB431542 (TGF-β
receptor I kinase inhibitor –an activator of the Smad
pathway). This confirms that asiaticoside induces type
I collagen synthesis through the activation of Smad
pathway in a TβRI kinase-independent manner.
The influence of asiaticoside on collagen synthesis
and keloid-derived fibroblast proliferation was also
investigated by Tang et al. (2011). Keloid scars occur as
results of a pathological wound healing, characterized
by hyperproliferation of keloid fibroblasts, overproduction
of extracellular matrix, aberrant cytokine and growth
factor activities. The TGF-βpathway, especially TGF-β1,
is involved in keloid formation. Prolonged healing of the
wound can lead to unbalances in TGF-β1 expression and
thus can cause fibroproliferative disorders and excessive
scar formation. Within R-Smad family, Smad3 mainly me-
diates collagen production in dermal fibroblasts stimu-
lated by TGF-β. Overexpression or overphosphorylation
of Smad in keloid fibroblast in comparison with normal
fibroblasts was observed. The asiaticoside inhibits the
TGF-βreceptors protein and mRNA expression,
increases the Smad7 protein and mRNA expression,
whereas it did not alter Smad2, Smad3, Smad4, expres-
sion and phosphorylated Smad2 and Smad3 (reduction
of TGF-βR1 expression leads to the decreased expression
of R-Smads) in keloid scars. Smad7, as Smads inhibitor,
acts as a negative feedback regulator which is antagonist
of R-Smads. Taken together, it seems that asiaticoside
has a dual role by promoting wound healing and
preventing scar formation.
The ethanolic extract of C. asiatica enhanced three-
fold collagen synthesis of human fibroblast cells com-
pared to the control. The highest collagen synthesis
was found at 50 mg/mL of C. asiatica extract. This ex-
tract demonstrated significant DPPH-radical scavenging
activity with 84% inhibition at a concentration 1 mg/mL.
The activity was compared to that of grape seed extract
and vitamin C (Hashim et al., 2011).
The ursane triterpenoids suppressed the production of
NO and secretion of TNF-αin lipopolisaccharide stimu-
lated RAW 264.7 cells; therefore, these compounds are
considered to be important anti-inflammatory constituents
of C. asiatica. Among the analyzed compounds, asiaticoside
presented the strongest effect (Nhiem et al., 2011).
The influence of asiaticoside on normal human skin
cells was studied by Lee et al. (2012). In vitro studies
proved that asiaticoside affects proliferation of human
skin dermal fibroblasts as well as increases migration
rates and accelerates attachment of skin cells.
Ruszymah et al. (2012) studied the effect of the aque-
ous extract of C. asiatica on re-epithelization of corneal
epithelium during wound healing. It has been proven
that the extract significantly enhances the migration of
rabbit corneal epithelial (RCE) cells in the in vitro
Extract/compound Model/effect/route of application
a
Reference
Hexane, methanolic, ethyl
acetate and water extracts
Incision and burn wounds/↑wound healing/topical application in rats Somboonwong et al., 2012
Asiaticoside LPS-treated rats/anti-inflammatory, antipyretic activity
(↑TNF-α, IL-6, COX-2, PGE2, liver myeloperoxidase,
↓IL-10, up-regulation heme oxygenase-1)/oral administration in rats
Wan et al., 2013
CLINICAL TRIALS
Madecassol® tablets Patients with systemic and localized scleroderma/positive
effect of treatment
Guseva et al., 1998
Madecassol® ointment
Extract of C. asiatica
(50 mg asiaticoside/capsule)
Wound healing in diabetic patients; 200 patients, randomized
study/shorten healing than in placebo group
Paocharoen, 2010
a
only in in vivo studies; ECM - extracellular matrix; DPPH - 2,2-diphenyl-1-picrylhydrazyl; COX-2 - prostaglandin-endoperoxide synthase 2
(cyclooxygenase-2); IL-1 - interleukin 1; IL-6 - interleukin 6; IL-10 - interleukin 10; LPS - lipopolysaccharide; VEGF - vascular endothelial
growth factor; MCP-1 - monocyte chemotactic protein-1; TNF-α- tumor necrosis factor alpha; PGE2 - prostaglandin E2; TTFCA - total
triterpenoid fraction of C. asiatica; TECA - titrated extract of C. asiatica.
Table 2. (Continued)
1120 W. BYLKA ET AL.
Copyright © 2014 John Wiley & Sons, Ltd. Phytother. Res. 28: 1117–1124 (2014)

wound healing model. At high concentration, it also has
an antiproliferative action on the RCE cells.
Asiaticoside enhanced periodontal tissue healing on
human periodontal ligament cells (HPDLs). Dose-
dependent increases in the levels of mRNA and protein
of fibronectin and type I collagen, as well as attenuated
metalloproteinase-I mRNA expression, were observed
when HPDLs were treated by asiaticoside. Further-
more, asiaticoside promoted osteogenic differentiation
of HPDLs (Nowwarote et al., 2013).
The various fractions from methanolic extract of C.
asiatica showed significant antibacterial and antifungal
activity against a various microorganisms (Gram-positive,
Gram-negative bacteria and fungi) (Ullah et al., 2009;
Dash et al., 2011).
Psoriasis. The anti-psoriatic activity of water extracts of
C. asiatica, containing asiaticoside and madecasosside on
the growth of SVK-14 keratinocytes, was compared with
those of water extracts of Psoralea corylifolia seeds
containing psoralen and synthetic dithranol. The tests were
performed on two types of C. asiatica and P. corylifolia
extracts: (i) with addition of polyvinylpolypyrrolidone
(PVPP) and (ii) without PVPP responsible for the re-
moval of phenolic compounds. The extracts inhibited
keratinocyte replication with IC
50
values of (i) 209.9 ±
9.8 μg/mL, (ii) 238.0 ± 2.5 μg/mL for C. asiatica and (i)
18.4 ± 0.6 μg/mL, (ii) 36.3 ± 3.3 μg/mL for P. corylifolia.
These results proved that phenolic compounds were not
responsible for the inhibitory effect of the extract. The
IC
50
value of dithranol, asiaticoside and madecasosside
was 1.2 ± 0.1 μg/mL, 8.0 ± 0.5 μg/mL and 8.4 ± 0.1 μg/mL,
respectively. It is worth to note, that although the aqueous
extract of the C. asiatica herb was not as potent as that of
the P. c o r y l i f o li a seed, its constituents, i.e. triterpenoid
glycosides, had IC
50
values similar to those of dithranol
(Sampson et al., 2001).
In vivo experiments
Wound healing. When applied topically, 1% ointment,
cream and gel with aqueous extract of C. asiatica, three
times a day for 24 days on the open wounds in rats,
increased cellular proliferation and collagen synthesis
at the wound site, as evidenced by the increase in colla-
gen content and tensile strength. The treated wounds
epithelialized faster and the rate of wound contraction
was higher as compared to control wounds. The process
of healing was the best with gel formulation
(Sunilkumar et al., 1998).
The activity of C. asiatica was studied in relation to
normal and delayed-type wound healing in guinea pigs.
The animals were treated with 0.2% solution of
asiaticoside applied to punch/puncture wounds. After
treatment, there was an increase in hydroxyproline
content of about 56% and in tensile strength of about
57%. Moreover, an increase in collagen content and
better epithelization were reported. A similar effect
was obtained in the same animal model by oral adminis-
tration of asiaticoside (1 mg/kg of body weight), as well
as in guinea pigs with experimentally induced diabetes
characterized by delayed-type wounds treated with
0.4% asiaticoside solution (Shukla et al., 1999a).
The wound healing process depends on antioxidants
levels in the wound. After 7 days of twice daily
application of asiaticoside (0.2%) on incisional wound
in rats, the levels of enzymatic and non-enzymatic anti-
oxidants, e.g. superoxide dismutase (35%), catalase
(67%), glutathione peroxidase (49%), vitamin E (77%),
and ascorbic acid (36%), in the newly created tissues were
elevated (Shukla et al., 1999a, 1999b).
Wounds treated with TECA and its separated com-
ponents: asiatic acid, madecassic acid and asiaticoside
were investigated in wound chamber model by
Maquart et al. (1999). After the stainless steel wound
chambers were implanted under the skin of rats,
TECA and isolated compounds were injected. Cham-
bers were collected after 7, 14, 21 or 28 days and bio-
chemical and histological analyses were performed.
TECA-injected wound chambers were characterized
by the increased dry weight, DNA, total protein,
collagen, uronic acid and peptidic hydroxyproline
content, suggesting the increased remodeling of the
extracellular matrix in the wound. Presumably, the
tested extract and compounds caused fibroblast
proliferation and migration, as well as the production
and activation of some growth factors in the wound.
The triterpenoid components were also able to
stimulate the synthesis of glycosaminoglycans,
especially hyaluronic acid synthesis. The stimulating
effect on collagen synthesis in human skin fibroblasts
was demonstrated for asiaticoside, asiatic, madecassic
acid and their combination. However, asiaticoside
was active at lower doses than asiatic and madecassic
acids.
A mixture of asiatic and madecassic acids was tested
on the connective tissue of rats. Following subcutaneous
implantation of glass rods, the rats were administered
the triterpenic acids orally or subcutaneously. After
3 weeks, irrespective of the administration route, the
weight of granuloma of the scar tissue was reduced.
The rupture strength and tensile strength of the scar
tissue increased. The effect was associated with an
increase in the collagen content, as compared to the
uninjured tissue (Brinkhaus et al., 2000).
The ethanolic extract of the C. asiatica facilitated the
wound healing in both normal and dexamethasone-
suppressed wound. The study was done on Wistar al-
bino rats using incision, excision and dead space wounds
models. The extract increased the wound breaking
strength in incision wound model, the rate of wound
contraction and accelerated the epithelization compared
to control wounds. Wet and dry granulation tissue
weights, granulation tissue breaking strength and
hydroxyproline content in a dead space wound model
also increased significantly. The extract had the attenu-
ating effect of dexamethasone healing in all wound
models. The results were confirmed by histology obser-
vations (Shetty et al., 2006).
It was also found that madecassoside was active in
burn wound healing, through increasing antioxidative
activity and enhancing collagen synthesis, and influencing
angiogenesis. After oral administration of this compound
at doses 6, 12 and 24 mg/kg to mice facilitatation of
wound closure in a time-dependent manner and
complete wound closure took place on 20th day in the
group receiving 24 mg/kg of madecassoside. A histo-
pathological study showed that madecassoside could
alleviate infiltration of inflammatory cells and en-
hanced epithelization resulting from dermal prolifera-
tion of fibroblasts. The tested compound at doses 12
1121THE EXPERIMENTS ABOUT USE OF CENTELLA ASIATICA IN DERMATOLOGY
Copyright © 2014 John Wiley & Sons, Ltd. Phytother. Res. 28: 1117–1124 (2014)

and 24 mg/kg decreased nitric oxide level and malonyl
dialdehyde content in the burned tissue. Madecassoside
increased the level of reduced glutathione and hydroxy-
proline, an indicator of collagen synthesis in burned
skin. These results confirm a positive effect on fibro-
blast proliferation and collagen synthesis during burn
wound repair. The authors indicate that the effect of
madecassoside on wound healing involve a few mecha-
nisms including collagen synthesis, antioxidant activity
and accelerated angiogenesis, which play an important
role in the formation of new granulation tissue in the
proliferation (Liu et al., 2008).
Topical application of asiaticoside at a dose of 10 pg,
1 ng or 100 ng/wound area for 20 days on the backs of
mice, caused facilitation of burn wound healing through
the influence on the level of various cytokines produced
in the place of the burn wound. The improvement in
burn wound healing might be an outcome of angiogene-
sis promotion during wound healing in the injured area
occurring as a result of the stimulation of vascular endo-
thelial growth factor production. This happens as a re-
sult of an expression increase in monocyte chemotactic
protein-1 (MCP-1) in keratinocytes and interleukin-1β
(IL-β) in macrophages induced by asiaticoside and
MCP-1 (Kimura et al., 2008).
The effect of different C. asiatica extracts on the inci-
sion and burn wound was studied in an experimental
animal study. All types of extracts used in the study:
hexane, methanolic, ethyl acetate and aqueous affect
the wound healing process, but the ethyl acetate extract
rich in asiatic acid was the most active (Somboonwong
et al., 2012).
Asiaticoside administered orally, exhibited the potent
antipyretic and anti-inflammatory effects in
lipopolisaccharide-treated rats. These effects could be
associated with the inhibition of pro-inflammatory me-
diators, including TNF-αand IL-6 levels, COX-2 protein
expression and PGE2 production, as well as liver
myeloperoxidase activity. Furthermore, asiaticoside
increases the level of antiinflammatory IL-10 in serum
and up-regulates heme oxygenase-1 (HO-1) expression,
an enzyme which protects the liver (Wan et al., 2013).
Clinical study
Wound healing. C. asiatica extract can shorten the
healing process of wound in diabetic patients. The ran-
domized control study included 200 diabetic patients,
treated with two capsules of C. asiatica extract (50 mg
asiaticoside/capsule) three times a day. Results showed
that wound contraction was better than in the placebo
group. Moreover, the extract suppresses the formation
of scar tissue (Paocharoen, 2010).
Scleroderma. Guseva et al. (1998) studied the efficacy of
orally/topically administered madecassol in patients
with systemic sclerosis (SSc) and localized scleroderma
(LS). They found that 6 month oral course (30 mg/day)
caused softening of the skin lesions, lightening of
hyperpigmentation and improvement of general condi-
tion of 12 SSc patients. The drug was not effective in
patients with progressive disease and in those with diffuse
skin lesions. The best response was observed in the area
of digital ulcers in SSc patients.
TOXICITY
C. asiatica applied in the recommended doses is not
toxic and the possible side effects are rare. It may cause
allergic reactions and burning, when used externally.
Oral administration of the recommended doses of C.
asiatica may cause dyspepsia, nausea and headache,
and overdose may result in dizziness and drowsiness.
Gotu kola can cause an increase of glucose level in the
blood of diabetic patients, as well as lipids level in the case
of coexisting hyperlipidemia (Gruenwald et al., 2004).
There are data suggesting the risk of hepatotoxicity of
C. asiatica in humans treated for 20–60 days (Jorge and
Jorge, 2005).
Treatment with C. asiatica extracts for more than
6 weeks is not recommended and a 2-week break before
the next application must be maintained. No informa-
tion is available about interactions of preparations
containing C. asiatica with other drugs, teratogenic
effect on the fetus and safety of use by lactating women;
hence, preparations containing extracts of this herb are
not recommended at this time (Gohil et al., 2010).
DISCUSSION
It has been scientifically proven that C. asiatica herb can be
useful in the treatment of skin diseases, especially in
wound healing. Different extracts (TECA, TTFCA,
ethanolic and methanolic), as well as individual pentacyclic
triterpenes, mainly asiaticoside, madecassoside, asiatic and
madecassic acid were investigated. Due to the fact that the
studies were carried out on defined extracts, undefined
extracts and individual compounds, the results are difficult
to compare. However, the evaluation of main compounds
activity allows to conclude that the active constituents are
pentacyclic triterpenes.
Most in vitro studies were carried out using human
dermal fibroblasts. It was proven that C. asiatica has a
great impact on extracellular matrix proteins deposition.
It stimulates fibroblasts proliferation, activates Smads
pathway, increases the collagen synthesis, decreases
the activity of metalloproteinases and thus increases
the collagen deposition (Tenni et al., 1988; Maquart
et al., 1990; Bonté et al., 1994; Bonté et al., 1995; Lu
et al., 2004a, 2004b; Hashim et al., 2011; Tang et al.,
2011; Nowwarote et al., 2013). It also inhibits the inflam-
matory phase of wound healing (Nhiem et al., 2011).
Furthermore, the anecdotic studies provide information
on proangiogenic (Coldren et al., 2003), antioxidative
(Hashim et al., 2011; Nhiem et al., 2011) and antimicro-
bial (Ullah et al., 2009; Dash et al., 2011) activity of C.
asiatica extracts. Taken together, all the above-
mentioned activities may improve the healing process
of wounds and therefore they give a mandate for further
in vivo studies.
The studies which elucidate the mechanism of wound
healing such as changes of gene expression involved in
angiogenesis and the activation of Smad pathway
provided important information on the effectiveness of
asiaticoside as a major active constituent of C. asiatica
(Maquart et al., 1999; Nhiem et al., 2011). It can be
assumed that the detected mechanism may be represen-
tative of Gotu kola.
1122 W. BYLKA ET AL.
Copyright © 2014 John Wiley & Sons, Ltd. Phytother. Res. 28: 1117–1124 (2014)

There is also one in vitro study focusing on anti-
psoriatic effect of C. asiatica by Sampson et al. (2001).
The results are promising but unfortunately there are
no other studies supporting them. Therefore, there is a
need of more studies, preferably in the form of clinical
trials to prove the efficacy of C. asiatica as an anti-
psoriatic agent.
Most of the studies on animal models were focused on
wound healing. They indicated that C. asiatica increases
collagen synthesis, as well as proliferation and migration
of fibroblasts and thus accelerates the reepithelization
and contraction of the wound (Sunilkumar et al., 1998;
Shukla et al., 1999a; Maquart et al., 1999; Brinkhaus
et al., 2000; Liu et al., 2008). The efficacy was supported
by histology findings (Sunilkumar et al., 1998; Shetty
et al., 2006; Liu et al., 2008). Moreover, C. asiatica was
responsible for antioxidative, anti-inflammatory and
proangiogenic activity according to a few studies (Shukla
et al., 1999a, 1999b; Kimura et al., 2008; Liu et al., 2008;
Wan et al., 2013). Together with the in vitro studies, it
makes C. asiatica a good candidate to clinical trials with
chronic wounds. Unfortunately, there is just one clinical
trial on diabetic patients with wounds (Paocharoen,
2010). However, good clinical response was observed,
thus confirming that C. asiatica is a potent agent promot-
ing wound healing. The other clinical trial was focused on
the assessment of efficacy of C. asiatica in SSc and LS pa-
tients. It seems that the prominent benefit obtained by
oral, as well as topical administration of madecassol was
healing of the digital ulcers (Guseva et al., 1998). This
may rather confirm the efficacy of madecassol in wound
healing than in improving of sclerodermic lesions.
In conclusion, although previous studies suggest a
positive effect of Gotu kola on wound healing, more
studies are needed. Current knowledge is insufficient
to clearly determine the effectiveness of C. asiatica and
its preparation in facilitating the wound healing. More-
over, available literature does not clarify the best route
and dosage of administration of the C. asiatica extract.
In order to evaluate the usefulness of the plant in this
area, clinical trials should be carried out. However, con-
sidering the safety of C. asiatica, it should be mentioned
that proangiogenic activity of topically applied agents
could be connected to the higher risk of neoplasm
formation (Griffioen and Molema, 2000). As the
proangiogenic activity of C. asiatica was proved, caution
should be maintained in clinical trials.
Conflict of Interest
The authors declare that there are no conflicts of interest.
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