The majority of pharmacological investigations on C. asiatica focused on the triterpene’s wound-healing and venotonic activity.

•  In one of the early pharmacological investigations of centella,Boiteau and Ratsimamanga demonstrated that asiaticoside substantially hastened the healing of experimentally induced wounds.These authors concluded that asiaticoside worked selectively in stimulating the rapid and healthy activity of the reticuloendothelial system.

•  Additional studies on the mechanisms of action of centella to enhance wound healing showed that asiaticoside, given orally, by intramuscular injection, or by implantation to rats, mice, guinea pigs, and rabbits, produced a wide range of effects (Box 64.1).

• The efficacy of centella in stimulating collagen synthesis was demonstrated in human tissue cultures. Interestingly, this research demonstrated an additional benefit when vitamin C was added to the experimental cultures.

•  The outcome of centella’s complex actions is a balanced multiphasic effect on cells and tissues participating in the process of healing, particularly in connective tissues. Enhanced development of the normal connective tissue matrix is perhaps the prime therapeutic action of C. asiatica.

• Centella was shown to enhance the connective tissue structure of the perivascular sheath, reduce sclerosis, and improve blood flow through the affected veins.

• Research has also demonstrated positive effects of centella on the central nervous system, cognitive function, stress, and anxiety. The major effects are an enhancement of cholinergic mechanisms and a significant antioxidant action via increasing glutathione levels.
  Presumably, these mechanisms are responsible for the improvements in mental function noted in both animal and clinical trials. Excellent results in improving cognitive function and memory were seen in animal models of Alzheimer’s disease.

• Ethanolic and methanolic extracts of C. asiatica have shown significant protection and lowered blood glucose to normal levels in glucose tolerance tests carried out in alloxan-induced diabetic rats.

• Water extract has a chemopreventive effect on colon tumorigenesis, and asiaticoside might be useful in cancer chemotherapy because it induces apoptosis and enhances the antitumor activity of vincristine in cancer cells.

• Animal studies also demonstrate cardioprotective activity against cardiomyopathy in rats, and results strongly suggest the cardioprotective activity of the plant in limiting ischemia-reperfusion-induced myocardial injury through preservation and restoration of the antioxidant defense system. Centella was also shown to possess other diverse pharmacological effects in experimental models, including antiulcer, antimicrobial, immunomodulatory, and spasmolytic activity.

Clnical Applications

Burns

The standardized extract from C. asiatica has been used effectively in the treatment of patients with second- and third-degree burns caused by boiling water, electrical current, or gas explosion. Daily local application, intramuscular injections of the extract, or both, resulted in
excellent results when treatment was started immediately after the accident. The extract prevented or limited the shrinking and swelling of the skin caused by skin infection, and it inhibited scar formation, increased healing, and decreased fibrosis. A randomized controlled
study compared the efficacy of silver sulfadiazine versus Centiderm (an ointment made from an ethanol extract of fresh C. asiatica leaves) in patients with partial-thickness burns from October 2014 to February 2015 in Iran. Burn wounds were treated once daily, and patients followed up daily with a burn specialist until the wounds were completely
healed, with subjective and objective variables recorded on days 3, 7, and . The use of Centiderm ointment not only improved the objective and subjective findings in less than 3 days but also improved the reepithelialization and complete healing times (about 7 days sooner
compared with placebo).

Cellulite and Striae Gravidarum

Cellulite, known as liposclerosis, is a noninflammatory change within the subcutaneous adipose tissue caused by an increase in the volume of fat cells or by the increased division of connective tissue, which causes constriction of small blood vessels. Treatments for cellulite
involve preparations that affect the adipose and connective tissue and improve microcirculation; they can be used topically, internally, and or transdermally.
The effect of centella in the treatment of cellulite appears to be related to its ability to enhance connective tissue structure and reduce sclerosis by acting directly on fibroblasts. Madecassoside, an extract from C. asiatica, is known to induce collagen expression and/or modulate inflammatory mediators. Triterpenes of C. asiatica increase the metabolism of lysine and proline, the amino acids that build collagen, and increase the synthesis of tropocollagen and mucopolysaccharide in the connective tissues, thus improving the nutrition of tissues and providing connective vascular stimulation. In several clinical studies, standardized extracts of C. asiatica demonstrated good results in the treatment of cellulite and the prevention of stretch marks during pregnancy. In the treatment of cellulite,
Bourguignon observed the action of the extract on several types of cellulite in 65 patients who underwent other therapies without success. Over a period of 3 months, good results were produced in 58% of the patients and satisfactory results in 20%. A study of 60 people with cellulite evaluated the influence of Madecassol® applied four times a day for 4 months. Results clearly showed a beneficial effect of the gotu kola extract on inhibiting the progression of cellulite and a significant improvement in the skin condition in 85% of the experiment participants.
A randomized, double-blind, placebo-controlled trial of the cream Trofolastin®, containing an extract of C. asiatica, α-tocopherol, hydrolyzed collagen, and elastin, was carried out on 100 pregnant women. The cohort was split evenly between the treatment group and the placebo group. After 30 months of treatment, striae occurred in 56% of the placebo group compared with 34% of the treated group; this difference was statistically significant. In women with a history of striae during puberty, the active cream induced a significant absolute
prevention in 89% of the cases, whereas in the placebo group, all the women developed striae.

Cirrhosis of the Liver

Darnis et al. reported on the therapeutic use of an extract of C. asiatica in alcohol-induced cirrhosis (six patients), cirrhosis of unknown etiology (two patients), and chronic hepatitis. In the cirrhosis patients, improvement in the histological findings and regression of inflammatory
infiltration were observed. No effect was observed in the patients with chronic hepatitis. Other reports supported the use of centella in fibrotic conditions of the liver.

Keloids

Keloids and hypertrophic scars are characterized by a prolonged inflammatory phase that may go on for months or even years without progressing to the maturation phase. The inflammatory phase is characterized histologically by large numbers of immature, swollen
collagen bundles intermingled with inflammatory debris, whereas the maturation phase is characterized by mature fibrocytes, normal collagen fibers, and few inflammatory cell elements.
The standardized extract of C. asiatica demonstrated impressive clinical results in the treatment of keloids and hypertrophic scars.

The mechanism of action appears to be multifaceted but is primarily
the result of reducing the inflammatory phase of scar formation while
simultaneously enhancing the maturation phase of scar formation.
Asiaticoside has been shown to downregulate the expression of TGF-
β1 mRNA and tissue inhibitors of metalloproteinases-1 and upregulate
TGF-β3 mRNA expression, resulting in the ability to decompose
the products of type I collagen and reduce hypertrophic scars.26 It has
been further proposed that asiaticoside interferes with scar formation
by increasing the synthesis of acidic mucopolysaccharides and
increasing the activity of myofibroblasts. In one study, 227 patients
with keloids or hypertrophic scars were treated by oral administration
with a standardized centella extract (effective dosage 60–90 mg). The
centella extract was used alone in 139 patients (the curative group),
and 88 used the extract along with surgical scar revision (preventive
group).In the curative group, 116 patients (82%) were found to have
benefited from the extract after 2 to 18 months, either by relief of their
symptoms or by the disappearance of the inflammatory phase. In a
double-blind substudy of 46 of the 139 patients, 22 of 27 receiving the
extract improved, whereas only 9 of 19 given a placebo improved. In
the preventive group, the centella extract also demonstrated a significant
positive effect. The therapeutic course in these patients began
a few weeks before surgery. If a positive response was observed, the
patient was brought to surgery and kept on the centella extract for 3
months. (This method of preselection allowed the researchers to offer
other forms of therapy to unresponsive patients.) Clinical improvement
was observed in 72 of the 88 patients (79%).

Kidney Disease

Traditional Chinese medicine has used gotu kola to treat kidney diseases
for centuries. Its direct benefits for the kidneys have only been
shown in animals but are encouraging. In rats, gotu kola showed a protective effect from Adriamycin-induced nephropathy, resulting in dramatically improved kidney function. Another study combined gotu
kola in conjunction with naringenin and showed decreased fibrosis
formation in the kidneys.

Leprosy

Several investigators reported impressive clinical results using C. asiatica
and its extracts (oral, intramuscular, or topical) in the treatment
of leprosy in both uncontrolled and controlled studies. The therapeutic
response was comparable to that of dapsone, the standard allopathic
drug used in the treatment of leprosy.
In addition to its wound-healing activity, it appears that oxyasiaticoside,
an oxidized form of asiaticoside, inhibited the growth of the
tubercle bacillus in vitro and in vivo by dissolving the waxy coating of
Mycobacterium leprae.

Improving Mental Function and Quality of Life

The neuropharmacological properties of C. asiatica have been extensively studied. Mechanisms of action for its efficacy in memory disorders involve antioxidant, free radical scavenging, and cholinergic
modulatory activities. Although long used to promote improved mental
function, the first clinical investigation involving centella significantly
increased the mental abilities of 30 developmentally disabled
children. After a 12-week period, the children were more attentive
and better able to concentrate on assigned tasks.
Based on historical use and clinical studies, centella may also help
improve mental function and quality of life in the elderly. Eighty
elderly subjects participated in a double-blind study and were randomly
assigned to receive placebo or standardized extract of C. asiatica
at doses of 250, 500, and 750 mg once daily for 90 days. The subjects
were evaluated to establish baseline data of physical performance using
the 30-second chair-stand test, hand-grip test, and 6-minute walk test.
The health-related quality of life was assessed using a standard questionnaire.
These assessments were repeated every month throughout
the 3-month experimental period using the aforementioned parameters.
Moreover, 1 month after the cessation of C. asiatica treatment, all
subjects were also evaluated using these parameters again. The results
showed that after 2 months of treatment, C. asiatica at doses of 500
and 750 mg/day increased lower extremity strength assessed via the
30-second chair-stand test. In addition, the higher doses of C. asiatica
improved the life satisfaction subscale within the physical function
subscale. Therefore the results from this study appear to support the
traditional reputation of C. asiatica on strength improvement, especially
in the lower extremities of the elderly. C. asiatica also possesses
the potential to be a natural resource for increasing vigor and strength
in healthy elderly persons.
Asiatic acid exerts a significant neuroprotective effect on cultured
cortical cells by potentiation of the cellular oxidative defense mechanism,
which may prove efficacious in protecting neurons from the oxidative
damage caused by exposure to excessive glutamate. The plant
accelerates nerve regeneration and contains multiple active fractions
that increase neurite elongation in vitro, suggesting that components
in centella may be useful for accelerating repair of damaged neurons.
Centella is also being investigated for its potential in Alzheimer’s
disease as an inhibitor of β-amyloid (Aβ) formation. Water extracts
of C. asiatica inhibit phospholipase A2 (PLA2) enzymes, particularly
cPLA2 and sPLA2, which play key roles in Aβ-induced neurotoxicity.
Further studies on the water extract found that caffeoylquinic acids act
as the active substances preventing Aβ-induced cell death by enhancing
mitochondrial biogenesis in conjunction with activating antioxidant
response genes and normalizing calcium homeostasis.
Relieving Anxiety
Centella is viewed as an anxiolytic on the basis of in vitro models and
emerging clinical evidence. An early study was conducted in humans to
measure the effect of centella on reducing the acoustic startle response.
After a single administration of centella, subjects experienced a significantly reduced acoustic startle response compared with the placebo—a clear indication of significant antianxiety action. In an open clinical study in patients with generalized anxiety disorder, a 70% hydroethanolic extract of C. asiatica (500 mg/capsule, twice daily, after meal) was shown to significantly (P < 0.01) attenuate anxiety-related disorders and reduce the stress phenomenon and depression.

Scleroderma

A standardized extract of C. asiatica was tested in several trials in
the treatment of scleroderma (including systemic sclerosis). In
addition to decreasing skin induration, patients noticed a lessening
of arthralgia and improved finger motility. Presumably, the positive
therapeutic response was a result of centella’s eutrophic effect on
connective tissue, thereby preventing the excessive collagen synthesis
observed in scleroderma.

Venous and Microcirculatory Disorders

The most well-documented clinical utility for a standardized extract
of C. asiatica is in the treatment of chronic venous insufficiency,
venous hypertension, and microcirculatory disorders. The effect
of Centella in venous insufficiency and varicose veins appears to be
related to its ability to enhance connective tissue structure, reduce sclerosis, and improve blood flow through the affected limbs. Asiaticoside
has been shown to improve microcirculation and reverse fibrosis in
humans with varicose veins. 3, 5-Di-O-caffeoylquinic acid, a constituent
of gotu kola, has been found to display an antithrombotic and

inhibitory effect on dynamic coagulation. This is significant when
one considers that fibrin clots play a pivotal role in cardiovascular
conditions.
In the treatment of chronic venous insufficiency, significant
improvement in symptomatology (e.g., feelings of heaviness in the
lower legs, paresthesias, nocturnal cramps), physical findings (e.g.,
edema, telangiectasias, trophic ulcers, vein distensibility), and functional
capacity (improved venous flow) was observed in approximately
80% of patients in the clinical trials.
In studies of patients with venous hypertension (ambulatory
venous pressure >42 mm Hg), detailed evaluations using laser Doppler
flowmetry, transcutaneous oxygen, and carbon dioxide tension measurements and the determination of capillary filtration rate, ankle
circumference, and ankle edema, along with detailed symptom evaluation, clearly demonstrated that centella extracts were clinically effective in dealing with this disorder.
The standardized extract of C. asiatica also showed an ability to
improve diabetic microangiopathy, it prevented the edema and microcirculation alterations seen during medium- to long-distance flights,
and it normalized the echographic character of carotid arteries with
significant plaque.

Wound Healing

Standardized extracts of C. asiatica were shown in many clinical studies
to greatly aid wound repair. The types of wounds healed include
the following:
• Surgical wounds, such as episiotomies and ear, nose, and throat
surgeries
• Skin ulcers caused by arterial or venous insufficiency
• Traumatic injuries to the skin
• Gangrene
• Skin grafts
• Schistosomiasis lesions
• Perineal lesions produced during childbirth

Dosage

Daily dosages of the various forms of centella are as follows:

• Standardized extract (40% asiaticoside, 29%–30% asiatic acid,
29%–30% madecassic acid, and 1%–2% madecassoside): 60 to 180
mg/day
• Crude dried plant leaves: 2 to 4 g/day
• Tincture (1:5): 10 to 20 mL/day
• Fluid extract (1:1): 2 to 4 mL/day

TOXICOLOGY

C. asiatica and its extracts are well tolerated, especially orally.1,2 There
is one report of three case histories of women (61, 52, and 49 years old)
who developed jaundice after taking C. asiatica for 30, 20, and 60 days,
respectively. However, there was little description or validation of the
product in question. Nonetheless, the hepatic lesions were quite significant on biopsy (granulomatous hepatitis with marked necrosis and
apoptosis, chronic hepatitis with cirrhotic transformation and intense
necroinflammatory activity, and granulomatous hepatitis). All patients
improved with C. asiatica discontinuation and ursodeoxycholic acid
10 mg/kg per day.
The topical application of a salve containing centella was reported
to cause contact dermatitis, although quite infrequently.
Although the oral administration of asiaticoside at a dose of 1 g/kg
body weight was not proved toxic in toxicology studies, the toxic dose
of asiaticoside by intramuscular application to mice and rabbits was
reported as 40 to 50 mg/kg body weight.
Asiaticoside was implicated as a possible skin carcinogen when
repeated applications were used in an experimental animal model.
Teratologic studies using the extract in rabbits proved negative.