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CENTELLA ASIATICA

Pharmacological Review on Centella asiatica: A Potential Herbal Cure-all

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116297/

Abstract

In recent times, focus on plant research has increased all over the world. Centella asiatica is an important medicinal herb that is widely used in the orient and is becoming popular in the West. Triterpenoid, saponins, the primary constituents of Centella asiatica are manly believed to be responsible for its wide therapeutic actions. Apart from wound healing, the herb is recommended for the treatment of various skin conditions such as leprosy, lupus, varicose ulcers, eczema, psoriasis, diarrhoea, fever, amenorrhea, diseases of the female genitourinary tract and also for relieving anxiety and improving cognition. The present review attempts to provide comprehensive information on pharmacology, mechanisms of action, various preclinical and clinical studies, safety precautions and current research prospects of the herb. At the same time, studies to evaluate the likelihood of interactions with drugs and herbs on simultaneous use, which is imperative for optimal and safe utilization of the herb, are discussed.

Plants have been used as treatments for thousands of years, based on experience and folk remedies and continue to draw wide attention for their role in the treatment of mild and chronic diseases. In recent times, focus on plant research has increased all over the world and a large body of evidence has been accumulated to highlight the immense potential of medicinal plants used in various traditional systems of medicine[1–3]. Centella asiatica (CA) is a very important medicinal herb used in the orient[4], which is also becoming popular in the West[5]. Commonly known as mandukparni or Indian pennywort or jalbrahmi, it has been used as a medicine in the Ayurvedic tradition of India for thousands of years and listed in the historic ‘Sushruta Samhita’, an ancient Indian medical text[6,7]. The herb is also used by the people of Java and other Indonesian islands. In China, known as gotu kola, it is one of the reported “miracle elixirs of life” known over 2000 years ago[7]. CA or gotu kola should not be confused with kola nut as it does not contain any caffeine and has not been shown to have stimulant properties. In the nineteenth century, CA and its extracts were incorporated into the Indian pharmacopoeia, wherein in addition to wound healing, it was recommended for the treatment of various skin conditions such as leprosy, lupus, varicose ulcers, eczema, psoriasis, diarrhoea, fever, amenorrhea, and diseases of the female genitourinary tract[8].

Despite large number of studies reported over the past decades on the evaluation of biologically active components and their mechanisms of action, the outcome of these studies is still unsatisfactory. Although there have been several claims regarding the underlying mechanisms involved in the biological actions of this herb, more scientific data are needed to justify its ever increasing use. Therapeutic potential of this plant in terms of its efficacy and versatility is such that further detailed research would appear momentous. The present review incorporated a detailed account of the plant, stressing its therapeutic uses, pharmacology, mechanisms of action based on preclinical and clinical studies, safety issues along with the current research potential of the herb. A high quality and reliable medical information from the internet was retrieved only from the Health-on- Net (HON) conduct-certified and accredited websites like Entrez PubMed (Medline), CAM-PubMed, Allied and complementary medicine database, Natural Medicine Comprehensive Database, Embase and Cochrane library. The databases were searched up to the year 2009 for the latest information on the herb.

MECHANISMS OF ACTIONS BASED ON PRECLINICAL STUDIES

Wound healing:

The CA extracts (CAE) have been used traditionally for wound healing and the research has been increasingly supportive for these claims[8]. A preclinical study reported that various formulations (ointment, cream, and gel) of an aqueous CAE applied to open wounds in rats (3 times daily for 24 days) resulted in increased cellular proliferation and collagen synthesis at the wound site, as shown by an increase in collagen content and tensile strength[17]. The authors found that the CAE-treated wounds epithelialized faster and the rate of wound contraction was higher when compared to the untreated control wounds. Healing was more prominent with the gel product. It is believed to have an effect on keratinization, which aids in thickening skin in areas of infection[18]. Asiaticoside, a constituent in CA, has been reported to possess wound healing activity by increasing collagen formation and angiogenesis[19,20]. Apart from showing a stimulation of the collagen synthesis in different cell types, the asiaticoside were shown to increase the tensile strength of the newly formed skin, furthering the healing of the wounds. Also, it was shown to inhibit the inflammatory process which may provoke hypertrophy in scars and improves the capillary permeability[19,20].

In one laboratory animal study, the effects of asiaticoside on antioxidant levels were examined, as antioxidants have been reported to play a role in the wound healing process[21]. The authors concluded that asiaticosides may have enhanced the induction of antioxidants at an initial stage of wound healing, but continued application of the preparation seemed not to increase the antioxidant levels in wound healing. The activity of asiaticoside has been studied in normal as well as delayed-type wound healing[22]. In guinea pig punch wounds topical applications of 0.2% solution of asiaticoside produced 56% increase in hydroxyproline, 57% increase in tensile strength, increased collagen content and better epithelisation. In streptozotocin diabetic rats, where healing is delayed, topical application of 0.4% solution of asiaticoside over punch wounds increased hydroxyproline content, tensile strength, collagen content and epithelisation thereby facilitating the healing. Asiaticoside was active by the oral route also at 1 mg/kg dose in the guinea pig punch wound model.

It promoted angiogenesis in the chick chorioallantoic membrane model at 40 μ/disk concentration. In one study, effects of oral and topical administration of an alcoholic extract of CA on rat dermal wound healing were evaluated[22]. The extract increased cellular proliferation and collagen synthesis at the wound site, as evidenced by increase in DNA, protein and collagen content of granulation tissues. Quicker and better maturation and cross linking of collagen was observed in the extract-treated rats, as indicated by the high stability of acid-soluble collagen and increase in aldehyde content and tensile strength. The extract treated wounds were found to epithelialize faster and the rate of wound contraction was higher, as compared to control wounds. These results indicated that CA produced different actions on the various phases of wound repair by exhibiting significant wound healing activity in normal as well as delayed healing models[23].

Venous insufficiency:

One of primary effects of CA was postulated to be on connective tissues by strengthening the weakened veins[24]. It was postulated that CA might assist in the maintenance of connective tissue[25]. In the treatment of scleroderma, it might also assist in stabilizing connective tissue growth, reducing its formation as it reportedly stimulated the formation of hyaluronidase and chondroitin sulfate, as well as exerted a balancing effect on the connective tissue[25]. CA was reported to act on the connective tissues of the vascular wall, being effective in hypertensive microangiopathy and venous insufficiency and decreasing capillary filtration rate by improving microcirculatory parameters[26].

Sedative and anxiolytic properties:

CA was described to possess CNS effects in Indian literature such as stimulatory-nervine tonic, rejuvenant, sedative, tranquilizer and intelligence promoting property[27]. It has been traditionally used as a sedative agent in many Eastern cultures; the effect was postulated mainly due to the brahmoside and brahminoside constituents, while the anxiolytic activity is considered to be, in part due to binding to cholecystokinin receptors (CCK B ), a group of G protein coupled receptors which bind the peptide hormones cholesystokinin (CCK) or gastrin and were thought to play a potential role in modulation of anxiety, nociception, memory and hunger in animals and humans[28].

Antidepressant properties:

The antidepressant effects of total triterpenes from CA on the immobility time in forced swimming mice and concentration of amino acid in mice brain tissue was observed. In the study, imipramine and total triterpenes from CA reduced the immobility time and ameliorated the imbalance of amino acid levels confirming the antidepressant activity of CA[29]. The same authors investigated the possible antidepressant effect of total triterpentes of CA by measuring the corticosterone levels in mice brain[30]. The contents of monoamine neurotransmitters and their metabolites in rats cortex, hippocampus and thalamus were evaluated wherein significant reduction of the corticosterone level and increase of the contents of 5-HT, NE, DA and their metabolites 5-HIAA, MHPG in rat brain were observed which further strengthened the postulated involvement of total triterpenes of CA in ameliorating the function of HPA axis and increasing the contents of monoamine neurotransmitters for its antidepressant effects.

Antiepileptic properties:

Asian CA increases the cerebral levels of GABA, which explains its traditional use as anxiolytic and anticonvulsant. The isolated steroids from the plant have been used to treat leprosy[31]. In one study, the effects of aqueous CAE (100 and 300 mg/kg) were evaluated on the course of kindling development, kindling-induced learning deficit and oxidative stress markers in pentylenetetrazole (PTZ) kindled rats[32]. Passive avoidance test and spontaneous locomotor activity, after 24 and 48 h after administration of PTZ, and oxidative stress parameters like malondialdehyde (MDA) and glutathione were carried out in the whole brain of animals. The administration of CA (300 mg/kg, p.o) decreased the PTZ-kindled seizures and showed improvement in the learning deficit induced by PTZ kindling as evidenced by decreased seizure score and increased latencies in passive avoidance behaviour. The findings suggested the potential of aqueous CAE as adjuvant to antiepileptic drugs with an added advantage of preventing cognitive impairment. The hydroalcoholic extract of CA leaves was also subjected to pharmacological screening using various experimental models and was found to show protective action against increase in intracranial electric stimulation (ICES) and chemo- convulsions, which includes pentylenetetrazol-induced convulsions, pentylenetetrazol-kindled seizures, and strychnine-induced opisthotonus tonic convulsions on oral administration[33]. It also showed a reduction in formation of lipid peroxidation products, reduction in spontaneous motor activity, potentiation in diazepam withdrawal-induced hyperactivity, hypothermia, and potentiation of pentobarbitone sleeping time. The extract (200 mg/kg body weight) completely inhibited pentylenetetrazol-induced convulsions. In pentylenetetrazol-kindled seizures and strychnine-induced convulsions, the extract showed protection at a dose of 100 mg/kg body weight. The doses of the extract selected for remaining studies were based on pilot studies, animal model used, and so forth. These findings suggested its potential anticonvulsant as well as antioxidant, and CNS depressant actions[33].

Cognitive and antioxidant properties:

CA is known to re-vitalize the brain and nervous system, increase attention span and concentration and combat aging[8]. A study demonstrated cognitive-enhancing and anti- oxidant properties of CA in normal rats. The effect of an aqueous CA extracts (100, 200 and 300 mg/kg for 21 days) was evaluated in intracerebroventricular (i.c.v.) streptozotocin (STZ)- induced cognitive impairment and oxidative stress in rats[34]. The rats treated with CA showed a dose-dependent increase in cognitive behaviour in passive avoidance and elevated plus- maze paradigms. A significant decrease in MDA and an increase in glutathione and catalase levels were observed only in rats treated with 200 and 300 mg/kg CA. As the oxidative stress or an impaired endogenous anti-oxidant mechanism is an important factor as implicated in Alzheimer›s disease (AD), cognitive deficits seen in the elderly and the i.c.v. STZ in rats has been linked to sporadic AD in humans. The cognitive impairment was associated with free radical generation in the model in the above study.

The findings reported in above study suggested the potential efficacy of CA in preventing the cognitive deficits, as well as the oxidative stress[34]. To throw more light on mechanism of these neuroprotection by CA, one recent study reported that the phosphorylation of cyclic AMP response element binding protein (CREB) was enhanced in both a neuroblastoma cell line expressing amyloid beta 1-42 (A beta) and in rat embryonic cortical primary cell culture[35]. In addition, the contribution of two major single components to the enhanced CREB phosphorylatioin was examined. Furthermore, inhibitors were applied in this study revealed that ERK/RSK signalling pathway (extra cellular signal-regulated kinase- ribosomal S6 kinase) might mediate this effect of CA extract. In another study, while, oral treatment with 50 mg/kg/day of crude methanol extract of CA for 14 days significantly increased the anti-oxidant enzymes, like superoxide dismutase (SOD), catalase and glutathione peroxidase (GSHPx) in lymphoma-bearing mice, the anti-oxidants like glutathione (GSH) and ascorbic acid were decreased in the animals[36]. In one study, derivatives of asiatic acid derivatives were shown to exert significant neuroprotective effects on cultured cortical cells by their potentiation of the cellular oxidative defence mechanism. Therefore, these agents were proved to be efficacious in protecting neurons from the oxidative damage caused by exposure to excess glutamate[37]. Another study demonstrated the protective effects of asiaticoside derivatives against beta-amyloid neurotoxicity when tested on B103 cell cultures and hippocampal slices. Out of 28 of the asiaticoside derivatives three components, including asiatic acid, showed a strong inhibition of beta-amyloid- and free radical-induced cell death. These derivatives may be candidates for a treatment of Alzheimer›s disease that protects neurons from beta-amyloid toxicity[38].

Gastric ulcer:

A laboratory study was reported in which aqueous extract of CA was found to be effective in inhibiting gastric lesions induced by ethanol administration[39]. The authors concluded that the CA extract presumably strengthened the gastric mucosal barrier and reduced the damaging effects of free radicals. Animal studies showed that CA extracts inhibited gastric ulceration induced by cold and restraint stress, in rats. The antiulcer activity was compared to famotidine (H 2 -antagonist) and sodium valproate (antiepleptic or antiseizure). Both the drugs and the herb extract showed a dose-dependent reduction of gastric ulceration, which, except for the antiulcer effect of famotidine, could be reversed with bicucullin methiodide (specific GABA a antagonist)[40]. It was postulated that CAE, which increased GABA levels in the brain, protected the rats against the cold restraint ulceration. Moreover, it is known that GABA and its agonists inhibit the central cholinergic action by affecting the turnover rate of acetylcholine in the rat brain[41]. Yet, another study was conducted to evaluate the possible anti- ulcerogenic activity of fresh juice of CA against ethanol-, aspirin-, cold-restraint stress- and pyloric ligation induced gastric ulcers in rats. The drug given orally in doses of 200 and 600 mg/kg twice daily for five days, showed significant protection against all the above experimental ulcer models and the results were comparable with those elicited by sucralfate (SF, 250 mg/kg, p.o., BD×5 days).

CA extracts showed little or no effect on offensive acid-pepsin secretion. However, at 600 mg/kg it significantly increased gastric juice mucin secretion and increased the mucosal cell glycoproteins signifying increase in cellular mucus. It also decreased cell shedding indicating fortification of mucosal barrier. Author concluded that the ulcer protective effect of CAE may be due to strengthening of the mucosal defensive factors[42]. One study showed that CA and its constituents, asiaticosides have an anti-inflammatory property that was brought about by inhibition of nitric oxide (NO) and thus facilitating ulcer healing[43]. Some other researchers also showed the efficacy of CA through preclinical and clinical studies for healing gastric ulcers[44,47]. CA has also been investigated to demonstrate its role in periodontal therapy[48].

Antinociceptive and antiinflammatory properties:

The effects of CA upon pain (antinociception) and inflammation in rodent models were reported[49]. The antinociceptive activity of the aqueous CAE (10, 30, 100 and 300 mg/kg) was studied using acetic acid-induced writhing and hot-plate method in mice[49], while the antiinflammatory activity of CA was studied by prostaglandin E2-induced paw edema in rats[49]. The aqueous CAE revealed significant antinociceptive activity with both the models similar to aspirin but less potent than morphine and significant antiinflammatory activity comparable to mefenamic acid. These results suggested that the aqueous CA extracts possesses antinociceptive and antiinflammatory activities which justified the traditional use of this plant in the treatment of inflammatory conditions or rheumatism[50]. Recently, antirheumatoid arthritic effect of madecassoside in type II collagen-induced arthritis (CIA) in mice was studied to investigate the therapeutic potential and underlying mechanisms of madecassoside on CIA[51]. Madecassoside (10, 20 and 40 mg/kg), orally administered from the day of the antigen challenge for 20 consecutive days, dose-dependently alleviated the severity of the disease based on the reduced clinical scores, and elevated the body weights of mice.

Also, a histopathological examination indicated that madecassoside alleviated infiltration of inflammatory cells and synovial hyperplasia as well as provided protection against joint destruction. Moreover, madecassoside reduced the serum level of antiCII IgG, suppressed the delayed type hypersensitivity against CII and moderately suppress CII-stimulated proliferation of lymphocytes from popliteal lymph nodes in CIA mice. In vitro, madecassoside was proved to be ineffective in the activation of macrophages caused by lipopolysaccharide[51]. It was concluded in the study that madecassoside substantially prevented mouse CIA, and might be the major active constituent of CA responsible for its clinical uses in rheumatoid arthritis and that the underlying mechanisms of action may be mainly through regulating the abnormal humoral and cellular immunity as well as protecting from joint destruction[51].

Miscellaneous uses:

A study reported the intracellular activities of an aqueous CAE against herpes simplex viruses, in vitro, containing both anti HSV-1 and antiHSV-2 activities[54,55]. Both the crude extract and purified fractions showed cytotoxicity against Ehrlich ascites and Dalton›s lymphoma ascites tumour cells, used in the study in a concentration-dependent manner. However, no cytotoxic effects were detected against normal cell lines.

The oral administration of the extracts (crude or purified) retarded the development of solid and ascites tumours in mice[56]. Antimycotic activity of CA was also reported[57]. The efficacy of CA in the treatment of depression, anxiety, and sleep disorders have been tested on small animals and are believed to be associated with its brahmoside and brahminoside constituents or saponin glycosides[58].