Current Updates on Centella asiatica: Phytochemistry, Pharmacology and Traditional Uses  

Dipankar Chandra Roy , Shital Kumar Barman , Md Munan Shaik
Department of Biotechnology and Genetic Engineering, Islamic University, Kushtia-7003, Bangladesh
Author    Correspondence author
Medicinal Plant Research, 2013, Vol. 3, No. 4   doi: 10.5376/mpr.2013.03.0004
Received: 14 Jan., 2013    Accepted: 22 Jan., 2013    Published: 28 Jan., 2013
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Dipankar C.R., et al., 2013, Current Updates on Centella asiatica: Phytochemistry, Pharmacology and Traditional Uses, Medicinal Plant Research, Vol.3, No.4, 20-36 (doi: 10.5376/mpr.2013.03.0004)

Abstract

Plants have been demonstrated extraordinary source of medicine, and recently focus on medicinal plant research has increased. Centella asiatica is well known for its traditional uses and medicinal properties for the treatment of many diseases. The published literatures mention the use of this plant as whole and bioactive compounds isolated are widely used in the treatment of various human ailments. C. asiatica reported to possess various pharmacological activities: antimicrobial activity, anticancer activity, wound healing activity, neuroprotechtive activity, immunomodulatory activity, anti-inflammatory activity, hepatoprotective activity, insecticidal activity, and antioxidant activity. C. asiatica is also rich in flavonoids and terpenoids compounds among them asiatic acid, asiaticoside, madecassoside is well characterized for its pharmacological value. The present review summarized widespread information on phytochemistry, isolated and characterized bioactive compounds, pharmacological properties, in vitro propagation and traditional uses of the important medicinal plant C. asiatica.

Keywords
Centella asiatica; Medicinal plants; Triterpenes; Terpenoids phytochemistry; Pharmacology; Neuroprotechtive activity; Wound healing actitivty; Anti-inflammatory activity; Anticancer activity

Medicinal plants are an important episode in the medical sector. Around 5 000 species have specific therapeutic value among 250 000 higher plant species on earth (Joy et al., 1998). Centella asiatica has a long history in ancient Ayurvedic remedy, used in wound healing, cleansing for skin problem and digestive disorders (Chevallier, 2001) and effective in treatment of stomach ulcers, mental fatigue, diarrhea, epilepsy, hepatitis, syphilis and asthma (Goldstein and Goldstein, 2012). Such traditional uses and reputation of this species cross over the boundary limit of Bangladesh, India, and Srilanka and now extensively used in the West (Chevallier, 2001; Meulenbeld and Wujastyk, 2001). C. asiatica and Hydrocotyle asiatica, belongs to familyApiaceae (Umbelliferae) are used synonymously and commonly known as Thankuni (Bengali), Bemgsag/Brahma-Manduki/Gotukola/Khu- lakhudi/Mandookaparni (Hindi), Indian Pennywort/ Marsh Pennywort/ Gotu kola (English) (Singh et al., 2010). C. asiatica is creeping, perennial herb with up to 2m long slender and tender horizontal reddish prostrate stolons, characterized by long rooting internodes (Jamil et al., 2007; Koh et al., 2009). Glabrous leaves, 1-3 arising from each node of the stems, are green, fan-shaped or round renifrom, 1.4 cm by 1.7 cm with crenate or dentate margin (Jamil et al., 2007; Koh et al., 2009). Flowers occurring in July- September are umbels with 3-4 white or light purple-to-pink petals bearing 4mm long oval to globular shaped fruit (Chauhan, 1999; Jamil et al., 2007; Koh et al., 2009). The most used part for medicinal purposes is dried whole plant, leaves and stems. C. asiatica plant is indigenous to Bangladesh, India, West Pakistan, China, Japan, America and the pacific (Koh et al., 2009). This plant is commonly seen in moist, sandy or clayey soils waste places (Jamil et al., 2007).

Phytochemistry
C. asiatica is a rich source of amino acids, flavonoids, terpenoids, essential oils, alkaloids etc. (Table 1). Most of the phytochemical studies concentrated on leaves and the constituents vary depending upon the geographical distribution (Chong and Aziz, 2011).

 
Table 1 Chemical constituents of C. asiatica

Bioactive compounds

C. asiatica is being used as a natural source of medicine for long time. The main active constitients of C. asitica are pentacyclic triterpenes (asiatic acid, madecassic acid, asiaticoside, and madecassoside, etc.) (Puttarak and Panichayupakaranant, 2012b). Two new dammarane monodesmosides centellosides A (1) and B (2), and two new natural products ginsenosides Mc (10) and Y (11), were reported recently (Weng et al., 2011; Han et al., 2012). An efficient microwave- assisted extraction method was developed for asiatic acid and a sensitive method for quantification of it and madecassoside in rat plasma also reported (Han et al., 2012; Nasir et al., 2012; Puttarak and Panicha- yupakaranant, 2012a). Asiatic acid has shown numerous therapeutic activities and biotransformation of it by Penicillium lilacinum ACCC 31890, Fusarium equiseti CGMCC 3.3658, and Streptomyces griseus CGMCC 4.18 strains was investigated and structure were deduced for all new derivaties (Guo et al., 2012). The ELISA method was investigated as an analytical tool for quality control and standardization of pharmaceutical products containing asiaticoside and madecassoside (Juengwatanatrakul et al., 2011; Tassanawat et al., 2012). Bioactive compounds isolated and characterized from C. asiatica are summarized in Table 2 with their physical properties.

 
Table 2 Structure and biological activities of bioactive compounds isolated from C. asiatica

Pharmacological Activity
The primary constituents of C. asiatica is the triterpenic fractions which showed wide range of defensive and therapeutic effects, most prominently influencing of collagen production and deposition in wound healing. Titrated Extract of Centella asiatica (TECA) is used to treat several microcirculatory problems, skin inflammation (eczema, atopic dermatitis, leprosy, varicose ulcers, etc.) fever, intestinal problems and genitourinary conditions (Belcaro et al., 2011). C. asiatica exerts diverse pharmacological activities such as antibacterial, antidepresent, antiemetic, antineo- plastic, antioxidant, antithrombotic, anxiolytic, gastroprotective, immunomodulatory, antigenotoxic, nerve regenerative, reproductive, wound healing etc. due to the presence of several saponin constituents, including asiaticoside, asiatic acid, madecassic acid and some other bioactive compounds (Craker and Simon, 1986; Koh et al., 2009; Kim et al., 2011).
Anti-inflammatory activity:Asiatic acid and madecassic acid showed anti-inflammatory effect by the inhibition of enzymes (iNOS, cyclooxygenase-2 (COX-2)), interleukins (IL-6, IL-1β), cytokine tumor necrosis factor (TNF-α) expression through the down-regulation of NF-κB activation in lipopoly- saccharide (LPS) induced RAW 264.7 murine macrophage cells (Yun et al., 2008; Won et al., 2010). Madecassoside prevented collagen II (CII)-induced arthritis (CIA) in mice (Liu et al., 2008). Ethanolic extract of C. aiatica at dose 100 mg/kg of body weight showed anti-inflammatory activity in rats similar to standard Ibuprofen (George et al., 2009). 3,5-dicaffeoyl-4-malonylquinic acid, extract from C. asiatica demonstrated beneficial effect on inflammatory bowel disease in rats (Di Paola et al., 2010). In experimental animal asiaticoside dose inhibited LPS induced fever and inflammatory response, including serum TNF-α and IL-6 production, liver myeloperoxidase (MPO) activity, brain COX-2 protein expression and prostaglandin E(2) (PGE(2) ) production (Wan et al., 2012). Asiaticoside G was also reported having anti-inflammatory property in LPS-stimulated RAW 264.7 cells (Nhiem et al., 2011).
Anticancer activity: A large number of experimental reports proved that different solvent extracts of C. asiatica has anti-cancerous activity. In vitro study on HeLa, HepG2, SW480 and MCF-7 cell lines showed that methanolic extract had induced apoptosis in human breast cancerous MCF-7 cells (Babykutty et al., 2009). Water extracts induced apoptosis in colonic crypts and exerted chemopreventive effect on colon tumorigenesis in male F344 rats (Bunpo et al., 2004). Asiatic acidinduced apoptosis in human melanoma SK-MEL-2 cells (responsible for skin cancer) and SW480 human colon cancer cells (Park et al., 2005; Tang et al., 2009). Asiaticosideenhanced anti-tumor activity of vincristine in cancer cells (Huang et al., 2004). Constituents in the methanol extract inhibited the proliferation of human gastric adenocarcinoma (MK-1), human uterine carcinoma (HeLa), and murine melanoma (B16F10) cells (Yoshida et al., 2005).
Anticonvulsant activity: Oral administration of different extracts from C. asiatica for 1 week at a dose of 200 mg/kg of body weight of in pentylenetetrazol (induces seizure) induced ratsincreased the level of acetylcholine (neurotransmitter) and decreased the activity of acetylcholinesterase, causes perceptible changes in the cholinergic system which indicates the anticonvulsant activity (Visweswari et al., 2010).
Antidepressant activity: Total triterpenes from C. asiatica showed reduced immobility time and ameliorating the imbalance of amino acid levels in forced swimming mice indicate antidepressant activity (Chen et al., 2003). Total triterpenes from C. asiatica also ameliorated the function of hypothalamic- pituitary-adrenal axis (HPA axis), increased the contents of monoamine neurotransmitters in rat brain and reduced the corticosterone level in serum (Chen et al., 2005).
Antioxidant activity: C. asiatica possesses potent antioxidant activity, whichcanexerted neuropro- tective effect and effect against age related oxidative damage in rats brain (Subathra et al., 2005). The anti-oxidant enzymes, like superoxide dismutase (SOD), catalase and glutathione peroxidase (GSHPx) were significantly increased, and anti-oxidants like glutathione (GSH) and ascorbic acid were decreased in lymphoma-bearing mice after oral treatment with 50mg/kg of body weight per day of crude methanol extract of C. asiatica for 14 days (Jayashree et al., 2003). Administration of aqueous extracts of C. asiatica showed to counteract lead-induced oxidative stress male rats (Sainath et al., 2011). Flavonoid compounds were present in aqueous extract of C. asiatica, showed highest antioxidant property (Pittella et al., 2009). The antioxidant properties of essential oils and various extracts of this plant may be a great interest in food industry, since their possible use as natural additives. To study the antioxidant properties and phenolic compounds present in C. asiatica, the optimum brewing procedure was studied to use as herbal teas (Ariffin et al., 2011).
Antiulcer activity: C. asiatica showed significant protection against ethanol, aspirin, cold restraint stress and pyloric ligation induced gastric ulcers in rats when 200 mg/kg and 600 mg/kg of body weight of fresh juice was given orally twice daily for five days (Sairam et al., 2001). Water extract of C. asiatica containing asiaticoside were found to reduce the size of the acetic acid induced gastric ulcers in rats (Guo et al., 2004).
Anxiolytic activity: 12 g oral single dose of C. asiatica after 60 minutes significantly attenuated the acoustic startle response (ASR) in human (Bradwejn et al., 2000). The elevated plus maze (EPM) test for  5 minutes revealed that administration of standardized extract, methanol and ethyl acetate extracts as well as pure asiaticoside had imparted anxiolytic activity in rats (Wijeweera et al., 2006; Wanasuntronwong et al., 2012). Medication of 500 mg/capsule (concentrated lyophilized of 70% hydro-ethanolic extract of C. asiatica), twice daily, after meal for 60 days in 33 patient (18 male and 15 female; average age 33 years) in Kolkata (India) demonstrated that C. asiatica not only significantly had attenuated anxiety related disorders but it also significantly had reduced stress phenomenon and its correlated depression (Jana et al., 2010).
Cardioprotective activity: Administration of alcoholic extract of C. asiatica at a dose of 1000 mg/kg of body weight in Laboratory bred Sprague–Dawley rats significantly reduced the necrosis of the myocardium (Pragada et al., 2004). C. asiatica extract demonstrated the cardioprotective effect at a dose of 200 mg/kg of body weight inadult male albino rats of Wistar strain on antioxidant tissue defense system during adriamycin induced cardiac damage (Gnana- pragasam et al., 2004). Madecassoside showed protective effect on myocardial ischemiareperfusion injury in rabbits and rats (Li et al., 2007; Bian et al., 2008).
Hepatoprotective activity:Total glucosides extract of C. asiatica showed significant anti-liver fibrosis effect in dimethylnitrosamine induced liver fibrosis in rats (Ming et al., 2004). Asiaticoside revealed hepatopro- tective effect against acute liver injury induced by lipopolysaccharide/D-galactosamine in mice (Zhang et al., 2010).
Effect on Skin:Asiaticoside stimulated skin aging inhibitor type 1 collagen synthesis in human dermal fibroblast cells and potential use in the treatment and/or prevention of hypertrophic scars and keloids was recommended (Lee et al., 2006; Tang et al., 2011b). Alcoholic extract of C. asiatica showed useful effects in pruritis and other skin disease (Gohil et al., 2010). Hydroalcoholic extract of C. asiatica was used to be made herbal creams along with four medicinal plants (Curcuma caesia, Areca catechu, Cinnamon zeylanicum and Tamarindus indica) which showed increased skin hydration, sebum levels, viscoelasticity, and decreased melanin content (Saraf et al., 2012). Asiaticoside promotes skin cell behaviours involved in wound healing by increasing migration rates of skin cells, enhancing the initial skin cell adhesion, inducing an increase in the number of normal human dermal fibroblasts (Lee et al., 2012). Aqueous extract of C. asiatica was nano-encapsulated with gelatin and efficiently reduced the expression of matrix metalloproteinase (MMP)-1 in UV-irradiated cells and inhibited hyaluronidase expression in mouse skin (Kwon et al., 2012).
Immunomodulating activity:Triterpenoid saponins of C. asiatica showed immunomodulatory effect (Plohmann et al., 1997). Methanolic extract of C. asiatica dramatically increased phagocytic index and total WBC in Swiss Albino mice (Jayathirtha and Mishra, 2004). Administration of water extract of C. asiatica significantly increased proliferation and the production of IL-2 and TNF-α in human peripheral blood mononuclear cells (PBMCs) but ethanol extract had inhibitory effect (Punturee et al., 2005). Asiatic acid and C. asiatica ethanol and dichloromethane extracts showed inhibitory effect on three major cDNA, which expressed human cytochrome P450 (CYP2C9, CYP2D6 and CYP3A4) isoforms (Pan et al., 2010).
Radioprotective activity:Aqueous extract C. asiatica showed more radioprotective effect than standard drug “ondansetron” against conditioned taste aversion (behavioural perturbation) induced by 60Co-γ irradiation at low dose 2Gy in male rats (Shobi and Goel, 2001). Administration of 100 mg/kg of body weight of aqueous extract of C. asiatica, just 1 hour before irradiation with 8Gy 60Co- γ rays was found most radioprotective in Swiss Albino Mouse (Sharma and Sharma, 2002) and further study revealed that 100mg/kg of body weight of dried powdered extract of C. asiatica had found to be effective against modified 60Co-γ irradiation induced damage in the mouse liver (Sharma and Sharma, 2005). 70% ethanolic extract of C. asiatica significantly reduced radiation-induced damage to DNA (Joy and Nair, 2009). microRNA (miRNA) expression profiling analysis was used to evaluate the protective effects of C. asiatica against Ultraviolet B damage in human keratinocytes, disclosed that miRNAs with altered expression were functionally related with cell proliferation and inhibition of apoptosis, may prevent the skin damage (An et al., 2012).
Wound healing activity: A large number of reports have been found about the wound healing activity of C. asiatica (Temrangsee et al., 2011). Aqueous extract of C. asiatica was used to formulate ointment, cream and gel, which evaluate for wound healing in rats showed faster epithelialisation and higher rate of wound contraction (Sunilkumar et al., 1998). Dexamethasone suppressed wound in Wistar Albino rats could be healed by ethanolic leaf extracts as like as normal model (Shetty et al., 2006). In a recent study in 200 diabetic patients revealed positive result with C. asiatica extracted capsule without any adverse effect in the department of Surgery, Thammasat University Hospital (Paocharoen, 2010). Wound healing activity of asiaticoside was also reported in guinea pig model at dose 1 mg/kg of body weight and in the chick chorioallantoic membrane model at concentration 40 µg/disk (Shukla et al., 1999). The effects of asiaticoside in human periodontal ligament cells (HPDLs) proliferation, protein synthesis, and osteogenic differentiation were investigated and showed enhanced periodontal tissue healing (Nowwarote et al., 2012). At low concentrations aqueous extract of C. asiatica promote epithelium wound healing in rabbit corneal epithelial (RCE) cells (Ruszymah et al., 2012). Ultra-fine cellulose acetate fiber mats containing asiaticoside (in crude extract or pure substance) were prepared and evaluated for wound dressings and loaded herbal substances were found stable up to 4 months, promotes proliferation and upregulating the production of collagen of the seeded (Suwantong et al., 2010). The clinical efficacy and side effects of the oral C. asiatica extract capsule in the diabetic wound healing was investigated (Paocharoen, 2010). Madecassoside showed enhance wound-healing and diminish keloid formation in primary keloid-derived fibroblasts, originating from human earlobe keloids (Song et al., 2012).
Memory enhancing Activity:Since the ancient time, C. asiatica is used to enhance intelligence and improve cognitive function. Oral administration with 200 mg/kg of body weight aqueous extract during postnatal development stage increased brain function in juvenile and young adult mice (Rao et al., 2005). Enhanced working memory and improved self-rated mood were observed in 28 patients after higher dose administration of C. asiatiac extract preparations (Wattanathorn et al., 2008). Asiatic acids isolated from C. asiatica showed enhancing learning and memory properties in male Spraque–Dawley rats (Nasir et al., 2011b).
Burns: C. asiatica extract and its active constituents are very effective against burns caused by boiling water, electric current or gas exploitation. Combination of C. asiatica extract with an antibiotic was anti-infectious beside healing burns (Salas et al., 2005). Low dose 10−8% to 10−12% (w/w) of asiaticoside application facilitated repairing in mice burned wound (Kimura et al., 2008).
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