A Literature Review Of The Vulnerary Properties Of Centella Asiatica

Abstract

The plant Centella asiatica (CA) belongs to the parsley family, blooms in the month of August and September and is aboriginal to Southeast Asia India and China but also grows in Venezuela, Columbia, United States and Eastern Europe. The plant is commonly known as mandukparni or jalbrahmi or Indian pennywort and its use is evident in the Ayurvedic tradional medicinal history of India for about thousands of years. The whole plant can be utilised for medicinal purpose. The plant had been used in the western countries to treat the condition of leprosy, lupus, eczema, psoriasis, ulcers, fever and diarrhoea. The plant has recently been approved included in the modern medicine practice as an alternative therapeutic solution with undergoing clinical trials for testing memory among Alzheimer patients and as a topical remedy against skin wounds and ulcers. The plant is extremely effective in treating wounds such as infective wounds, burn wounds, post operative wounds and hypertrophic scars. The pharmacological compounds that may be considered responsible for wound healing are triterpene compounds such as madecassic acid, asiatic acid, madecassoside and asiaticoside. Therefore, the medicinal plant CA can be considered as an effective formulation for healing varied types of wounds such as burn wound, incision wound and hypertrophic scars. The pronounced effect was obtained on day 3, 10 and 14 of the application of extracts based on clinical trials. However, in relation to its application further research should be conducted with respect to toxicity and dosage dependent mechanism of the extracts.

Introduction

Plants had been included in the treatment procedure about 1000 years back for the chronic or mild ailment based on the experiences of folk remedies. The recent upsurge in the plant-based research is due to the immense evidences available of medicinal plants in the field of traditional medicines. The plant Centella asiatica (CA) is a brown and green leafy plant which belongs to the parsley family that generally grows near water resources. The flowers of this plant are light purple in colour and blooms in the month of August and September. The leaves of this plant are greenish yellow in colour and are edible in nature. The plant is aboriginal to Southeast Asia India and China but also grows in Venezuela, Columbia, United States and Eastern Europe. The plant is commonly known as mandukparni or jalbrahmi or Indian pennywort and its use is evident in the Ayurvedic tradional medicinal history of India for about thousands of years (Chevallier, et al, 1996; Diwan, et al, 1991; Bown, et al, 1995).

The whole plant can be utilised for medicinal purpose. The medicinal usage of the plant is mostly because it helps in the purification of blood, treats hypertension and enhances memory and longevity. Based on evidence of ayurvedic application of the plant it can also be used for the treatment of nerve cells and other emotional disorders such as depression (Hagemann, et al, 1996; Poizot, et al, 1978). Therefore, it is often referred as cognitive enhancer. The plant herb had been used in the western countries to treat the condition of leprosy, lupus, eczema, psoriasis, ulcers, fever and diarrhoea. The plant has recently been approved in the modern medicine practice as an alternative therapeutic solution with undergoing clinical trials for testing memory among Alzheimer patients and as a topical remedy against skin wounds and ulcers. It has been also referred as antipyretic, rheumatic, antiviral, antibacterial and diuretic drugs (Singh, et al, 1969; Heidari, et al, 2007).

The plant is extremely effective in treating wounds such as infective wounds, burn wounds, post operative wounds and hypertrophic scars. The pharmacological compounds that may be considered responsible for wound healing are triterpene compounds such as madecassic acid, asiatic acid, madecassoside and asiaticoside (Heidari, et al, 2007). The action of wound healing has been demonstrated by both the extracts and isolated triterpene compounds (Heidari, et al, 2007). These secondary metabolites enhance significantly the percentage of collagen and cell layer fibronectin. The most significant impact had been observed in the maturation of scar with the production of type I collagen, reduction of inflammation and production of myofibroblast. Another study demonstrated that wound treated with titrated extracts of CA and with the isolated components such as madecassic acid, asiatic acid and asiaticoside enhanced significantly the content of collagen, overall protein and peptic hydroxyproline (Srivastava, et al, 1997). Therefore, due to the increased proliferation of fibroblasts the cell migration from surrounding tissues have stimulated along with the activation of some growth factors within the wounds (Srivastava, et al, 1997; Parameshwaraiah, et al, 1998). It was also observed that the triterpenoid compounds activated glycosaminoglycan specifically the synthesis of hyaluronic acid. Other experimental clinical studies on rat models had demonstrated that the rate of wound contraction was higher among the treated group with CA extract in comparison to the control group (Parameshwaraiah, et al, 1998). The healing effect was found to be more prominent with gel-based product of plant as it affected the keratinisation which eventually resulted in the thickening of skin (Poizot, et al, 1978).

Therefore, the present study conducted a narrative or traditional literature review which is the all-inclusive, decisive and objective analysis of the existing knowledge on the the wound healing properties of medicinal herb Centella asiatica that may help in the recovery of the patients. The literature review is considered to be an essential part of the research process which guides the researchers to determine a theoretical framework also highlights the context of the present study. It can be also termed as a rapid systemic review.

Methodology & Methods

Research philosophies can be of two types: Positivism and Interpretivism. Here the utilization of Positivism explore theory will be increasingly suitable which expresses that the examination and understanding of the exploration information could get fruitful through the obtained truth and clear realities from verified sources. This specific methodology permitted the scientist to build up an explanatory psyche to examine about the concerned research issue. An organized and quantitative research approach was applied to taking care of the exploration issue. Fundamental review approach had been alluded to as the procedure with the end goal of the writing survey. It is finished by applying orderly technique procedures, for example, basic examination explore considers, investigation of the auxiliary information, and the information that had been delivered quantitatively and subjectively (Saunders, et al, 2018). This particular approach had been used to obtain a detailed and exhaustive analysis of all the available kinds of literature on the electronic databases based on the inclusion criteria.

This chapter will focus to summarise the methods used to answer the study question. Methodologies stipulate the details for using a specific research strategy and the explanation of the research process. The systematic review will be defined and the rationale for using this approach will be described.

Research will be based on randomised controlled trials, crossover trials, case studies, cohort studies, case studies, clinical audits, clinical outcome studies, surveys, interviews and systematic review. The research papers which will be used for literature review of the dissertation will involve animal model study and humans based clinical trial results. The data will be analysed in form of the literature review.

Research Aim: The aim of the study is to conduct a literature review of the vulnerary properties of Centella asiatica

Research Questions

1) What are the varied medicinal properties of the herb Centella asiatica?

2) What are the pharmacological constituents of the medicinal herb Centella asiatica that may contribute to the wound healing properties of the herb?

Research Hypothesis

H0: The medicinal herb Centella asiatica does not exhibit any wound healing property

H1: The medicinal herb Centella asiatica exhibits significant wound healing property

Search Strategy

The study is based on the secondary research to gather the evidence from the existing literatures. Essential examinations and deliberate audits are chosen dependent on the best comprehension of the focal research question. Reasonable sources were recognized in the wake of investigating different electronic databases which contains countless excellent peer survey substance, for example, Google Scholar PubMed, Medline, EMBASE, Taylor, Karger, EBSCO host, Ovid and Francis Online. Grey literatures databases, used by the specialist for looking through logical substance are Open Gray, Med Nar and GreyNet International. The inquiry was finished with limitation to the most refreshed substance up to the year 2019 so applicable and most recent substance can be accessible for the writing audit reason. All the in-text references of the resulted papers were also reviewed to analyse and evaluate the content of the relevant databases.

The research analyst utilized systems, for example, "truncation search" notwithstanding indicators for the words such as medicinal properties of Centella asiatica *, pharmacological constituents*, triterpenoid*, wound healing*, burn wounds*, incision wound* etc. This specific methodology has helped the analyst to acquire a wide scope of data from a few database sources. Again, the inquiry results were expanded with the utilization of Boolean operators for instance “OR”, “AND” for decreasing down the query items. An in-depth systemic review on the topic of the research has been conducted based on case-controlled, cohort and cross-sectional studies published within the past 10 years focusing on the medicinal property of the herb Centella asiatica and the pharmacological active constituents reported to have beneficial effect on varied types of wound healing. One particular limitation was faced by the researcher was the non-availability of the full-length document apart from the abstract due to the registration service particulars of the University.

Keywords: Centella asiatica, medicinal property, antioxidant activity, anxiolytic activity, anti-depressant property, cognitive function, skin ageing, venous Insufficiency and varicose Veins, diabetic mellitus and diabetic ulcers, epilepsy, Alzheimer’s Disease, pharmacological compounds, triterpenes, dosage, wound healing, burn wound, incision, post operative surgery.

Search History

A systemic review was organised based on the cohort studies, cross sectional studies and the case-controlled studies which got published within the last 10 years. The study focused on the wound healing property of the plant Centella asiatica and association with the active pharmacological constituents. The medicinal property of the plant was investigated in detail.

As suggested from previous pieces of literature that the vital step of the systematic review is to gather available evidences which can explain the research question. The pyramid of the hierarchy of literature guides the researcher to choose the study design which would provide effective evidence to support the hypothesis of the study (Refer Fig: 1).

Study Design:

As suggested from previous pieces of literature that the vital step of the systematic review is to gather available evidence which can explain the research question as it incorporate endeavours to discover however much as could be expected of the exploration which tends to the audit's examination question. This is significant if the audit's decisions are not to be over-affected by contemplates which are essentially the most straightforward to discover (typically communicated research, demonstrating the advantage of meditations). The pyramid of the hierarchy of literature guides the researcher to choose the study design which would provide effective evidence to support the hypothesis of the study.

Therefore, this study concentrated on several types of pieces of evidence to investigate the importance of the medicinal herb Centella asiatica and its therapeutic properties. Cohort studies can be both prospective and retrospective in nature. Cohort studies can be considered to be ideal to evaluate the link between the risk factors and the outcomes and they can be prospective or retrospective in nature. On the other hand, the case-control studies are retrospective in nature, and it compares the difference between two groups, i.e, one group having the problem and the other one is the control group (the problem does not persist). This type of study also helps to establish the link between the risk factors and the health outcome. The significance of the cross-sectional studies is that they give a clear conception about the exposure and the interesting outcome within the same time. The following parameters are considered to be the disadvantages for conducting the study: selection bias, time used up in the study, absence of follow up in the study (Rudmik and Soler, 2015). The benefits associated with this method of systemic review is that it applies analytical and scientific methods for identifying and selecting the research which in turn reduces any form of bias in the study along with the productions of accurate and reliable results and conclusions in relation to the research hypothesis of the study. The researchers can study a wide number of literature which sources to help them evaluate the fact properly and present it in an accurate manner. There are few drawbacks of using this approach by the researcher which includes that the researcher may find it difficult to compile the results at the end of the study as different researchers used different approaches to conduct their study (Rudmik and Soler, 2015). Therefore, the researcher was very attentive while compiling the results from a wide range of studies to ensure the accurate validity of the results.

Study selection:

The inclusion and exclusion criteria are developed once the research idea becomes familiar with the literature search. To characterize the exclusion and inclusion criteria the title of the article and conceptual framework ought to contain the catchphrases or the positive inquiry thingelements. Relevant search should be done to match the requisite of research question though it may not contain the keywords or the search items within the title or abstract of the articles. To characterize the rejection criteria, any examinations that are falling "out of extensionscope" for the study and not coordinating with the set research addresses would not be considered. Any writing not written in the English language would not be considered for the study reason. Therefore, all the pieces of literature based on the defined inclusion and exclusion criteria are considered for the literature review.

For this study the inclusion and exclusion criteria include:

The title of the research articles should match with the research questions and this ensures the accuracy the abstract that has to be studied. If the abstract seems to be suitable with the research hypothesis of the study, the entire full-length study will be done to perform a critical analysis. All the evidence will be included in the PRISMA flowchart in terms of retrieved, included and excluded studies (Lewis, et al, 2019; Liberati, et al, 2009).

Analysis of the data:

The study analysis is done by observational research method which is a qualitative research method. The analysis of the data is considered to be a challenging task as it is used to assess the quality of the study. The data will be analysed using the Quality Appraisal Tools (QAT) as suggested. There are varieties of Quality Appraisal Tools available which may be used to facilitate the process. For the present study the data analysis will be done based on the Critical Appraisal Skill Programme (CASP) to ensure a robust research. This particular tool helps to conduct critical analysis in a wide variety of settings which includes the public health. This is a set of 8 appraisal tool checklist-based approach designed to be used in an educational programme or in a workshop setting. This particular quality appraisal tool is used to analyse the Systematic Reviews, Randomised Controlled Trials (RCT), Case Control Studies, Diagnostic Studies, Clinical Prediction Rule, Cohort Studies and Qualitative studies. The tool helps in finding the right information by highlighting the searches from various types of sources which includes the secondary sources, bibliographic sources and the gray literatures. The appraising section of the tool focuses mainly on the validity and reliability of the scientific papers, the significance of the outcome and the application of the findings to the concerned research project. There are several standardised checklists available on this webpage and this can be downloaded. The section that deals with the “acting on the evidence” focuses on the application of the data findings to our own research hypothesis, thinking about the practicality of the issues which may affect our study.

There is a separate checklist which consist of about 10 -12 questions are available for the Systematic Reviews, Randomised Controlled Trials (RCT), Case Control Studies, Diagnostic Studies, Clinical Prediction Rule, Cohort Studies and Qualitative studies. The checklists are wide ranging which can give direction to any researcher and can also guide on the outcome of the study. The CASP works on the basis of a systemic process due to which the strengths and weakness of any study can be identified. It also guides the researcher in the study design approach and regarding the application of the study in the local context in a most cost-effective way. Study designs are exposed to a wide range of variables that develops bias in the study design and therefore it is recommended to use standard lists of checklists to ensure the quality of the study undertaken. Sticking to the guideline of CASP enhances the significance of the study along with its findings (Singh, 2013)

Risk of bias:

One of the predicted risks is a too informal between systematic review with review of literature. Systematic review is evidence based that looks into existing literature in detail and in a methodological fashion to answer a definite question and to recognize gaps in prevailing literature (Betanny-Saltikov, 2012). On the other hand, a narrative of literature is an overview of the knowledge available on the specific topic. Risk of Bias is defined as the risk or “a systemic error or deviation from the truth in the result or inference” of the study. It is viewed as replaceable with the inner legitimacy of the investigation and hence is characterized as "the degree to which the structure and direct of an examination are probably going to have forestalled inclination (bias)". The device, for example, ROBINS-E, ROBINS-1 and Cochrane device looks at about a blunder in the examination structure and furthermore inspect the result to evaluate the conceivable predisposition in the investigation. To inspect about the blunder in a randomized control study (RCT), advancement of the guideline and systematic review study with Cochrane apparatus is applied while in the event that when an observational investigation of a measure is contrasted and theoretical randomized control study the examination of the information is carried on by ROBINS-I device (Sterne, et al, 2016; Savovic, et al 2014; Higgins, et al, 2011). The study specifically looked at the risk that may acquire from selection bias, confuding bias, reserchers bias etc. The study selection was done strictly on the basis of inclusion and exclusion criteria as mentioned in the table format above to screen and narrow down the search.The tool examines the five different domains of bias such as attrition performance, selection, reporting and others.

Ethical considerations in the study

The research analyst conducting the survey ought to pronounce about the potential irreconcilable circumstance and all the creators of the included investigation should be certified to stay away from any types of the demonstration of copyright infringement (Wager and Wiffen, 2011). No ethical consideration is required for study involving only literature review as per the guidelines of Lincoln College. Any work involving primary research must however still be submitted to the Ethics Committee. The data will be stored in an encrypted device with password protection system. The researchers who conducted clinical trials on animal models got the elthical clearance from the concerned Research Ethics Committee of the University before conducting the study.

Limitations of the study

As there is no financing funding accessible tto ensure the robustness of the present study by utilising additional strategies to reduce risk of bias such as: two independent investigators to perform the literature search, o lead the investigation, the confinements looked by the specialist is to get to the limited diaries and distributed information accessible on the electronic database important to the pursuit point. Moreover, the author may access the University library to access those evidence depending upon the registration of the University. The limitation of time can be managed by planning the study within the time allocatedconsidered as another limitation for the research for completion of educational studies. .

Centella asiatica is a traditional medicinal plant that exhibits therapeutic effects on wound healing of skin as supported by scientific studies. Apart from wound healing the plant can be used to treat various conditions of skin known as varicose ulcers, psoriasis, fever, diarrhoea, eczema, leprosy, amenorrhea, lupus and even the diseases of female genitourinary tracts. Though several studies had been conducted on the compositional analysis of the extracts of plants and the working mechanism, the final outcome of the studies are considered to be unsatisfactory. This demanded further research in this area in the future to evaluate the underlying mechanisms and also to justify its increasing use (Refer Fig: 2) (Gohil, et al, 2010; Hamidpour, et al, 2015).

The plant is reported to have varied types of medicinal properties. All are discussed in brief below:

Anxiolytic and Anti-depressant Properties

The plants have been traditionally used as remedy to anxiety disorder. Researchers have tested the application of the plant extracts on the anxiety symptoms of rats within varied test models such as open field test, social interaction test, elevated plus maze and on locomotor activities. The triterpene compound present within the extract was thought to be responsible for anxiolytic property via the novel environment test and Vogel test. Although there are other compounds present within the plant that may also correlate with the important pharmacological activities (Wijeweera, et al, 2006).

To evaluate the anti depressant activity of the total triterpenes, present in CA the parameters of immobility time and the concentration of amino acids in mice brain tissue was recorded. It was noted that there was reduction in the immobility time and improved the imbalance observed in the level of amino acids which confirmed the anti depressant activity of the plant (Selvi, et al, 2012).

Antioxidant activity

Our body gets damaged on daily basis due to the development of oxidative stress. Researchers had studied about the antioxidant activity of the plant and its positive impact upon physical satisfaction, emotional wellbeing, physical capability and outlook of healthy old adults. The authors reported that the plant CA could be considered as an herbal remedy responsible for increased physical capability among healthy volunteers because of the antioxidant property. The positive impact was observed within two months of the study period when they were administered with 500 and 750 mg/ CA daily (Mato, et al, 2011).

Learning and Cognition

A study reported about the positive impact of the plant CA on memory especially on learning and cognition. The rats were administered with aqueous extracts of the plant as the animals were participating in varied shuttle boxes and step through paradigms. It was noted that the extract lowered the avoidance response which indicated about the improved mechanism of learning and memory. Increasing doses of the extract such as 100, 200 or 300 mg/kg were administered and it also correlated with enhanced learning and cognition (Kumar, et al, 2002).

Alzheimer’s Disease

The aqueous extracts of the plant showed impact upon the nerve cells of prefrontal cortex, hippocampus and other areas of brain of new-born and adult mice model of study. Therefore, the author suggested the probable action of the aqueous extract of the plant upon degenerative impairments of memory, aging and learning due to alzheimer’s disease (Soumyanath, et al, 2012).

Antieplipeptic Properties

As reported CA of Asian origin had enhanced the level of GABA in the brain which confirmed its use as anticonvulsant and anxiolytic agents. Moreover, the steroidal compounds isolated from the plant had been used for the treatment of leprosy. To evaluate the efficacy of the plant as antiepileptic drug aqueous extract of CA was used to investigate on the course of kindling development, learning deficit stimulated by kindling and the markers of oxidative stress in the pentylenetetrazole (PTZ) kindled rats. The test for passive avoidance and spontaneous activity of locomotor was carried after 24 and 48 hours of administration. It was noted that with the administration of the extract of CA the PTZ-kindled seizures got reduced and improvement was also observed in the field of learning deficit stimulated with PTZ kindling. Thus, with reduced seizure score and enhanced latencies observed in the behaviour of passive avoidance confirmed the use of aqueous extract of CA as antiepileptic drug and for the prevention of cognitive impairment (Visweswari, et al, 2010).

For the treatment of diabetes mellitus

The plant CA can be considered as a strong candidate for the treatment of diabetic patients and also helps to arrest the continued progression of the disease because of the varied pharmacologically active compounds. In an experimental study, the rats were organised into seven different groups and were administered with a mixture of asiatic acid dissolved in 5% DMSO solvent, glibenclamide and water. The findings reported that there was an increased content of haemoglobin observed which might have been due to improved level of glycemic control because of Asiatic acid (Ramachandran, et al, 2013).

For the treatment of diabetic ulcers

The healing property of CA was evaluated on diabetic foot ulcers in a randomized control single centre study involving both type 1 and type 2 diabetic patients along with Wagner grade 3 post surgery foot ulcers. The study findings suggested that CA cream could be considered as an effective alternative cream for wound dressing (Ramachandran, et al, 2013; Kuo, et al, 2012).

For the treatment of venous Insufficiency and varicose veins

Some studies had reported about that CA had shown positive effects on reduction of abscess and enhanced the flow of blood that reduced the symptoms of the disease. An experimental study involving patients was conducted to evaluate the effect of plant CA on biochemical parameters of the patients with varicose veins. It was noted that the level of uric acids and lysosomal enzymes within the serum have reduced after the application (Chong, et al, 2013).

For the reduction of Skin Ageing

The experimental study conducted by few authors reported that the extracts of CA acted upon the connective tissues of the vascular walls. It was also noted that the plant could progress the parameters of microcirculation with the effective lowering of filtration of capillary system during the condition of venous insufficiency and hypertensive microangiopathy. Thus, the plant can be considered as a potential candidate for the reduction of skin ageing (Hussin, et al, 2007).

The pharmacological constituents of the plants and correlation with wound healing activity

The most important pharmacologically active constituents of the plants are triterpenoids or also known as saponins which comprises of asiaticosides (a trisaccharide molecule linked with aglycone asiatic acid, madasiatic acid and madecassoside. Other active constituents of the plant CA are brahmoside and brahminoside might have regulatory actions upon central nervous system and uterorelaxant action which is yet to be confirmed with the help of clinical studies (Brinkhaus, et al, 2000). The saponins and their isolated sapogenins are reported to be primarily responsible for the healing of wounds and vascularisation by the production of collagen at the site of wound. The crude extract of the plant is also reported to contain glycosides compounds such as thankuniside and isothankuniside responsible for antifertility action among mice models. Active constituent centelloside and its associated derivatives are reported to have significant effect in the treatment of venous hypertension (Antognoni, et al, 2011; Gohil, et al, 2010). Moreover, the total extracts of the plant contains the other pharmacologically important compounds such as sterols, phytosterols such as sitosterol, campesterol and stigmasterol, flavonoids, tannins (20 -25%), essential acid which constitutes of 0.1% beta-chariophylen, germachrene D and trans-beta-pharnesen, free forms of amino acids which includes aminobutyrate, glutamate, lysine, alanine, aspartate, serine, treonine; alkaloid namely hydrochotine; flavonoids such as chercetin and kempferol derivatives; vallerine which is a bitter compound and fatty acids such as linolnelic, linoleic, palmitic acids, oleic, stearic acids (Hamidpour, et al, 2015; Parameshwaraiah, et al, 1998).

Several pharmacological, clinical and biochemical studies have reported the use of defined and undefined alcoholic, aqueous extracts of the plant for the treatment of several types of wounds such as burn wound, infective wound and also post-operative wounds (Parameshwaraiah, et al, 1998; Rosen, et al, 1967; Shukla, et al, 1999). A study demonstrated the wound healing property of plants for both dexamethasone suppressed and normal wounds using Wister albino rat models for the experiments (Shukla, et al, 1999). The different wound models that were used for the study were excision, incision and dead space wounds. It was noted that the extract enhanced the parameter of wound breaking strength particularly in the incision wound model which in turn stimulated the wound contraction rate and epithelisation process (Rosen, et al, 1967). In case of the dead space wounds the granulation tissue and hydroxyproline content had also increased and it had also attenuated the healing effect of dexamethasone among all the wound models studied within the experiments (Shukla, et al, 1999). The tritated extracts of plant are named as TECA, total fraction of triterpenoid of plant CA (TTFCA), containing both fraction of asiatic acid (30%), madecassic acid (30%) and asiaticosides (40%) and overall triterpenic fraction (TTF) which contains fractions of madecassic acid (60%), asiaticosides (40%) and asiatic acid. All the products are same extracts which are available commercially in the name of Madecassol®, Blastoestimulina® or Centellase® (Gohil, et al, 2010). The commercially available extract Madecassol® had demonstrated preventive action or healing property on burn wounds and post operative hypertrophic scars. The fraction madecassoside was very much effective in healing of burn wound via enhancing the antioxidative activity, synthesis of collagen and by showing effect upon angiogenesis. When the compound was administered orally at varied dosage of value 6 mg/kg, 12 mg/kg and 24 mg/kg upon mice, it assisted in the closure of wound in a time-oriented fashion. The overall closure of wound took place on the 20th day with the dosage of 24 mg/kg of compound madecassoside (Gohil, et al, 2010). It was observed that the compound was responsible for extensive proliferation of dermal fibroblasts along with increased level of hydroxyproline which is an indicator of the synthesis of collagen within the burn wounds. Therefore, this can be considered as a confirmed positive effect about the proliferation of fibroblast along with synthesis of collagen for the healing of burn wounds (Somboonwong, et al, 2012). Other experimental studies had also revealed that asiaticoside could also effectively enhance the content of hydroxyproline and collagen within the puncture wounds or delayed type wounds of guinea pig with experimentally induced diabetes. It resulted in increased tensile strength and better epithelisation as observed during wound healing. The fraction asiaticoside was active even after the oral application with dosage value of 1mg/kg (Bylka, et al, 2013; Brinkhaus, et al, 2000). It was stated by authors of the study for the case of burn wound healing that the isolated fractions of extracts were responsible for promotion of angiogenesis in the injured area due to increased stimulation of Vascular Endothelial Growth Factor (VEGF) production. Eventually contraction of wound occurs as a result of the activity of myofibroblasts (Refer Fig: 3) (Somboonwong, et al, 2012; Bossé, et al, 1979).

Fig: 3 A: Normal Skin; B: untreated wounded skin; C: wound treated with normal saline solution (control); D: Tween 20-treated wound (control); E: wound treated with CA hexane extract; F: wound treated with CA ethyl acetate extract; G: wound treated with CA methanol extract; H: wound treated with CA aqueous extract-treated wound; Ep: epidermis; Kt: keratin; FN: fibrinoid necrosis; Exd: exudates; F: hair follicle; Ede: edema (Source: Somboonwong, et al, 2012) .

Another experimental study reported that varied formulations of aqueous extracts of CA such as cream, ointment and gel when applied over the open wounds of rat for 3 times a day resulted in similar synthesis of collagen at the site of wound responsible for tensile strength. The rate of epithelisation and contraction of wound was faster in the wound among the rat groups using CA extract as gel in comparison to the untreated groups (Widgerow, et al, 2000; Maquart, et al, 1999; Shetty, et al, 2006). Asiaticoside-rich portion got from the ethanol concentrate of Centella asiatica above grounds parts was not harmful to the human dermal fibroblast (HDF) and human dermal keratinocyte (HaCaT) cells. No such significant IC50 was recorded at dosages somewhere in the range of 0.19 and 100 μg/mL as because the cell viability was found to be above 80% when study conducted upon humans (Azis, 2017). Few other study conducted upon human cell lines reported positive findings (Hou,2016). Another important aspect was that it inhibited inflammation which might provoke hypertrophy within the scars and also improved the capillary permeability. The increased level of cellular proliferation during the healing of wound was evaluated by the rising content of the hereditary material, protein and collagen within the granulation tissue (Maquart, et al, 1999). Rapid maturation and cross linkage of collagen was observed among rats treated with extracts of CA in comparison to control untreated groups (Shetty, et al, 2006). Therefore, it could be established that the extract had effect on the process of keratinisation that resulted that resulted in the thickening of skin at the site of infection (The European medicines agency 2015; World Health Organization, 1999)

Discussions

The medicinal plant Centella asiatica can be considered as an effective formulation for healing varied types of wounds such as burn wound, incision wound and hypertrophic scars. The healing property was attributed to the increased collagen content, the main protein of wound connective tissue and is responsible for providing tensile strength (Somboonwong, et al, 2012; Shukla, et al, 1999). Several studies conducted recently have agreed with the findings of previous studies that especially the ethanolic extracts of the herb CA, isolated triterpenoids or asiaticoside are responsible for the enhanced synthesis of collagen at the site of the wound and for providing tensile strength (Rosen, et al, 1967; Suguna, et al, 1996; Shukla, et al, 1999). The other physiological pathways that help in the process of wound healing are enhanced proliferation of fibroblasts, mucopolysaccharides which are acidic in nature, intracellular content of fibronectin and the mitotic cell division within the germ layer. All these physiological mechanisms increase the tensile strength of the newly formed skin and also inhibit the inflammation of the keloids and hypertrophic scars (Suguna, et al, 1996). The study involving mice models demonstrated that when the aqueous, ethanolic, methanolic or hexa acetate extracts were applied over the varied types of wounds prominent healing was achieved on Day 3, 10 and 14 when compared with the only vehicle control. The results were determined based on the cross examination of wounds, degree of healing and most importantly by histopathological examinations (Shukla, et al, 1999). To correlate with the pharmacological constituents the chief compound that was identified to be present within the ethylacetate extracts was asiatic acid which is actually responsible for the increased synthesis of collagen and healing the wound. Thin layer chromatography (TLC) examination of the extract also highlighted that the ethanolic extract contains β-sitosterol which is responsible for potential angiogenic activity. The healing effects of the ethanolic and methanolic extracts were observed on day 14 indicating that the combined effect of these two compounds shows effect at the later stage of wound healing. The other two isolated fractions of triterpenoids obtained within the methanolic extracts were asiaticoside and madecassocide also reported to stimulate the synthesis of type I collagen within the dermal fibroblast cells of human by activating the TGF beta receptor I kinase-independent Smad signaling pathway (Somchit, et al, 2004; Cheng, et al, 2000; Shetty, et al, 2006). The compounds also reported to enhance the antioxidant level within the punch wound model which stimulates the process of wound healing. Another compound also reported to facilitate the burn wound healing in the mice models is madecassoside (Shetty, et al, 2006). However, the components asiatic acid, β-sitosterol, madecassocide and asiaticoside were not reported to be present within the aqueous extracts of the plant investigated via TLC on day 14 (Somchit, et al, 2004). Another study reported the presence of a flavonoid compound in the aqueous extract of CA that helps to control the oxidative stress and hence helps in the healing process (Brinkhaus, et al, 2000; Antognoni, et al, 2011). Few other studies have also reported that with the application of extract of CA or its isolated fractions helps in the treatment of skin diseases such as scleroderma and psoriasis. Due to the above-mentioned properties the extracts of CA have found application within the cosmetics for cellulite, striae, scars of surgery and photoaging skin (Chen, et al, 2003; Somchit, et al, 2004). Moreover, the extracts of CA have shown to impact the growth and proliferation of cells at the site of injury thus replacing the damaged tissues responsible for cosmetic impairment (Cheng, et al, 2000). The extracts had been shown to modulate various growth factors such as fibroblast, endothelial and vascular factors responsible for wound healing though further research is required to chalk out the mechanism involving these factors. Similarly, more research is required to study the anti-inflammatory activities of the extracts of CA involved during the wound healing process. When the extracts of CA were applied within the recommended doses it does not reveal toxicity and the probable side effects are very low (Widgerow, et al, 2000). However, the reported adverse effects of extracts of CA were localised allergic reactions with sensation of burning mostly observed when applied topically. Moreover, the commercially available extracts of CA such as Madecassol® and Centelase® were reported to show skin problems such as eczema on the hands and fingers and symptoms of vesicular reaction along with pruritus within 20 days of application (Maquart, et al, 1999; Shetty, et al, 2006). Therefore, further investigation is required on the safety, effectiveness and tolerability parameters of the extracts and the isolated triterpenes (Maquart, et al, 1999). Another issue which has become a matter of concern is the improper application of herbal formulations which includes the extracts of CA due to lack of medical supervision and also due to the possible adverse interactions with the other drugs applied simultaneously (Widgerow, et al, 2000).

Conclusion

Thus the overall study on the medicinal properties of herb Centella asiatica revealed that plant has immense therapeutic properties in relation to age related cognitive impairments, various other nerve disorders such as Alzheimer’s disease, epilepsy and other physiological conditions such as diabetes mellitus, diabetic ulcers, venous insufficiency and varicose veins. The most important pharmacological constituents mentioned within the extracts of plants are triterpenoid compounds and the isolated fractions are asiaticoside, asiatic acid, β-sitosterol and madecassocide. These components help in the process of healing of wound by utilizing the varied physiological mechanisms such as synthesis of collagen, inhibition of inflammation, promotion of angiogenesis, stimulation of vasodilation, and reduction of oxidative stress of wound. The healing process had been related to the other growth factors such as fibroblast, endothelial and vascular endothelial factors though further research is required in this field to understand the mechanism involved. Various scientific studies had confirmed the aspect of wound healing of the medicinal herb CA such as of burn wounds, incision wounds and puncture wounds with experiments on rat models. The pronounced effect was obtained on day 3, 10 and 14 of the application of extracts. However, in relation to its application further research should be conducted with respect to toxicity and dosage dependent mechanism of the extracts. Ongoing clinical trials are carried on the issues of safety, tolerability and effectiveness of the extract and its isolated fractions. Few clinical studies have also stated that with the oral and topical application of the extract in a controlled manner helps in the healing of wound. The presences of various antioxidant compounds within the extract of CA have contributed in the development of herbal extracts as a potential remedy of various health disorders related to ageing.

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