Phytochemistry and pharmacology (consolidated from pharmacological reviews)

Primary Active Constituents: triterpenes derived from asiaticoside (which includes Asiatic acid, madecassoside, and madasiatic acid), brahmoside and brahminoside, and centelloside and its derivatives

Solubility of primary active constituents (determined from chemical structure in reference to Ganora 2009):

Triterpenes: Asiaticoside; Asiatic acid (aglycone) and Madecassic acid (aglycone) are both oil-soluble while Asiaticoside and Madecassoside are likely water soluble. Brahmoside, Brahminoside and Centelloside are aglycone triterpenes and therefore likely oil-soluble.

Whole plant extraction: abundant tannins, essential acid, phytosterols (campesterol, sitosterol, stigmasterol), mucilages, resins, free amino acids (alanine, serine, aminobutyrate, aspartate, glutamate, lysine, threonine), flavonoids (derivative of chercetin and kempferol), an alkaloid (hydrochotine), a bitter component (vallerine), and fatty acids (linoleic acids, linolnelic, oleic, palmitic, and stearic acids)

Amino acids: aerial have more glutamine and serine. Roots are rich in aspartic, glutamic, serine, threonine, alanine, lysine, and histidine

Mechanisms based on preclinical studies and found in a Pharmacological Review:

Wound healing – This has been shown by an increase in collagen content and tensile strength and wound contraction rate. Asiaticoside is considered to be the main active component for this purpose.

Sedative and anxiolytic – The sedative properties are considered to be due to the brahmoside and brahminoside constituents. The anti-anxiety properties are considered to be due in part to binding to cholecystokinin receptors which is a group of G protein coupled receptors.

Antidepressant – Mice trial evidence suggests that imipramine and total triterpenes from Gotu kola are effective antidepressants as they reduced anxiety response and balanced the amino acid levels in the mice. This was reconfirmed with a study on the corticosterone levels in mice brains.

Antiepileptic – Gotu kola increases cerebral levels of GABA, important for anxiolytic and anticonvulsant activity. Leprosy has been treated using the isolated steroids in Gotu kola.

Cognitive and antioxidant – Gotu kola has been known to increase attention span and concentration and combat aging in the brain and nervous system. In normal rats treated with 200 and 300 mg/kg Gotu kola, a significant decrease in MDA and an increase in glutathione and catalase levels was observed in a study. In a study examining the neuroprotective mechanism, 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. The ERK/RSK signaling pathway might be the pathway through which Gotu kola takes effect as determined in a study using inhibitors. In another study, anti-oxidant enzymes were significantly increased in lymphoma bearing mice with oral treatment of 50mg/kg/day of crude methanol extract for 14 days. In another study, asiatic acid derivatives were shown to have significant neuroprotective effects on cultured cortical cells due to their cellular oxidative defense mechanism against exposure to excess glutamate. These derivatives and others are being studied as potential treatments for Alzheimer’s disease because they could protect neurons from beta-amyloid toxicity.

Gastric ulcer – Gotu kola extracts and juice have shown significant protection against gastric ulcers by increasing cellular mucus and decreasing cell shedding in rats. Another study showed the facilitation of ulcer healing due to the inhibition of nitric oxide by constituent asiaticoside providing anti-inflammatory effects.

Antinociceptive and anti-inflammatory – Aqueous extractions of Gotu kola at varying concentrations were shown to have significant antinociceptive activity in rats similar to aspirin but less potent than morphine and significant anti-inflammatory activity comparable to mefenamic acid. A histopathological examination of the effects of madecassoside showed alleviated infiltration of inflammatory cells and synovial hyperplasia while also providing protection against joint destruction.

Radioprotection – A 100mg/kg dose of plant extracts increased the survival time of mice exposed to a sublethal dose of gamma radiation significantly along with significantly less body weight loss of the mice compared to mice treated with radiation only.

Other uses – A study demonstrated intracellular activities of an aqueous extract against herpes simplex viruses in vitro.

Clinical studies found in a Pharmacological Review:

Both in vivo clinical studies and human monolayer cell culture experiments have concluded that Asiatic acid influences collagen synthesis. Local application of extracts demonstrated the role of asiaticoside in the increased levels of antioxidants (enzymatic and nonenzymatic) implying accelerated wound healing. Asiaticoside promotes angiogenesis as seen in both in vivo and in vitro models, angiogenesis is important to wound healing because the newly formed blood vessels help the hypoxic wounds to attain normoxic conditions.

A high number of circulating endothelial cells were detected in cases of vascular injury, thrombosis, acute myocardial infarction, and other peripheral vascular diseases. In a clinical study for post phlebetic syndrome (PPS) patients receiving 90mg of Gotu kola triterpenic fraction daily in three divided dosages over the course of 3 weeks, patients showed a statistically significant decrease in circulating endothelial cells, indicating the integrity of vascular intima was protected. In another study with 94 patients with vascular insufficiency of the lower limbs, a statistically significant difference in favor of treatment groups (120mg/day and 60mg/day) was observed in the parameters checked for lower limbs and edema. The overall evaluation of the patients were positive compared to the placebo as well. In another study with 52 venous hypertension (pressure greater than 42 mmHg) patients treated in three groups (60 mg/day, 30 mg/day, and placebo) over 4 weeks, the treatment groups significantly improved in a concentration-dependent manner in the parameters tested while no significant changes were observed in the placebo or 10 control subjects.

In a placebo-controlled study of 100 pregnant woman comparing an application of a compound cream containing gotu kola extract, vitamin E (alpha tocopherol), and collagen-elastin hydrolysates to placebo, the compound cream was associated with fewer women developing stretch marks than in placebo. The compound cream was also shown to decrease scarring, appearing to be related to the stimulation of maturation of the scar by the production of type I collagen and the resulting decrease in the inflammatory reaction and myofibroblast production.

In a study to determine the effect of Gotu kola on cognitive function and mood, 28 participants under the age of 61 received either 250, 500, or 750 mg of extract daily or placebo. After 2 months, the greatest improvements in both mood and cognitive function were detected in the 750mg treatment group. A double-blind, placebo-controlled study of the anxiolytic effects of Gotu kola in human subjects was conclusive in suggesting that there is anxiolytic activity. In a study of elderly subjects (age 65 and above) using diagnostic tools to measure daily living and depression, the mean score after a twice daily dose of 500 mg for 6 months showed significant improvement.