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Gotu kola (Centella asiatica)


Gotu kola (Centella asiatica) Image
Synonyms / Common Names / Related Terms
Antanan gede, Asiatic pennywort, asiaticoside, asiatischer wassernabel, bavilacqua, Blasteostimulina®, brahmi, brahmi-buti, brahmi manduc(a) parni, calingan rambat, Centalase®, Centasium®, Centellase®, Centella coriacea, Centella asiatica triterpenic fraction (CATTF), coda-gam, Emdecassol®, Fo-Ti-Teng®, gagan-gagan, gang-gagan, HU300, hydrocotyle, Hydrocotyle asiastica, hydrocolyte asiatique, idrocotyle, Indian pennywort, Indian water navelwort, indischer wassernabel, kaki kuda, kaki kuta, kerok batok, kos tekosan, lui gong gen, Madecassol®, marsh penny, pagaga, panegowan, papaiduh, pegagan, pepiduh, piduh, puhe beta, rending, sheep rot, talepetrako, tete kadho, tete karo, thankuni, thick-leaved pennywort, titrated extract from Centella asiatica (TECA), total triterpenic fraction of Centella asiatica (TTFCA), Trofolastin®, tsubo-kusa, tungchian, tungke-tunfke, water pennyrot, white rot.

Mechanism of Action

Pharmacology:

  • Constituents: The purported active components of gotu kola, accounting for 1-8% of the constituents, include asiatic acid, madecassic acid, asiaticoside, asiaticoside A, and asiaticoside B.21 The leaves of Centella asiatica have also been reported to contain 170mg calcium, 30mg phosphorous, 3.1mg iron, 414mg potassium, 6.58mg beta-carotene, 0.15mg thiamine, 0.14mg riboflavin, 1.2mg niacin, and 4mg asorbic acid.21
  • Alzheimer's disease effects: Asiaticoside derivatives, including asiatic acid and asiaticoside 6, were shown to reduce hydrogen peroxide-induced cell death, decrease free radical concentrations, and inhibit beta amyloid cell death in vitro, suggesting a possible role for gotu kola in the treatment and prevention of Alzheimer's disease and beta amyloid toxicity.1
  • Antioxidant effects: Asiaticoside derivatives, including asiatic acid and asiaticoside 6, were shown to reduce hydrogen peroxide-induced cell death, decrease free radical concentrations, and inhibit beta amyloid cell death in vitro, suggesting a possible role for gotu kola in the treatment and prevention of Alzheimer's disease and beta amyloid toxicity.1
  • Anti-gastric ulcer activity: In rats, extract of Centella asiatica significantly inhibited gastric ulceration induced by cold and resistant stress, similar to the inhibition caused by famotidine and sodium valproate.5 The titrated extract of Centella asiatica (TECA) has been shown to have protective and therapeutic effects on gastric mucosal damage in rats.6 Fresh juice of Centella asiatica given in doses of 200 or 600mg/kg twice daily for five days was shown to have protective activity against gastric ulcers induced by ethanol, aspirin, cold-restraint stress, and pyloric ligation.7 The higher dose resulted in significantly increased mucin secretion and mucous formation, while significantly decreasing cell shedding.
  • Anti-inflammatory effects: In rats, Madecassol was shown to decrease the severity of radiation-induced dermatitis vs. control.14
  • Anti-fertility effects: Animal study shows a consistent reduction of fertility in female mice after the ingestion of isothankuniside and its derivative BK compound, both of which are isolated from Centella asiatica.2
  • Antimicrobial effects: An in vitro study of Centella asiatica powder found no activity against the acid-fastness or viability of M. tuberculosis, despite its use in the treatment of leprosy (M. leprae).17 A subsequent in vitro study found asiaticoside to have little microbicidal activity against M. tuberculosis or M. leprae; however, when incorporated into liposomal form, the microbicidal activity of asiaticoside was greatly increased.18 Centella asiatica extract and asiaticoside are active against herpes simplex virus in vitro.19,20
  • Antineoplastic effects: In vitro, partially purified fractions of Centella asiatica crude extract significantly inhibit proliferation of cancerous cells in a dose-dependent fashion, with no toxic effects to human lymphocytes.4 In mice, oral administration of both crude extract of Centella asiatica and partially purified fractions of the crude extract slow the development of solid and ascites tumors, and increase the lifespan of mice, with possible action directly on DNA synthesis.4
  • Anxiolytic properties: Bradwejn et al. performed a double-blind, placebo controlled trial to study the effects of gotu kola on acoustic startle response (ASR), a validated instrument used to measure levels of anxiety.11,12,13 At 30 and 60 minutes after intervention, subjects who consumed 12g dose of gotu kola (from crude herb capsules, Nature's Way Canada, Ltd.) mixed in 300mL of grape juice experienced a significant decrease in their ASR, suggesting the possible ability of gotu kola to decrease anxiety. The small sample size and use of healthy (non-anxious) subjects limit the application of these data, but do suggest that gotu kola may possess anxiolytic properties. Although gotu kola has been studied for anxiety, the exact mechanism of action remains unclear.
  • Cardiovascular effects: In an investigation of oral Centellase (TTFCA 60mg three times daily) to stabilize carotid plaques, it was reported that TTFCA regulated and modulated collagen production over the 12-month study period.22
  • Hepatic effects: A randomized controlled trial showed that a combination product (CognoBlend® containing Bacopa monneria, Gingko biloba, cat's claw, gotu kola, rosemary) may be an effective adjunct treatment for patients with liver cirrhosis, although a mechanism of synergistic action in this study is unclear.16
  • Hepatic effects (hepatotoxicity): Researchers have hypothesized that gotu kola may contain di- or triterpenic active principles, which can produce hepatic injury by promoting apoptosis and altering cell membranes.15
  • Neuroprotective effects: The effect of chloroform: methanolic (80:20) extract of Centella asiatica (CA; 100 and 200mg/kg), was evaluated on the course of free radical generation and excitotoxicity in monosodiumglutamate (MSG) treated female Sprague Dawley rats. The extract showed significant improvement in catalase, super oxide desmutase, and lipid peroxides levels in hippocampus and striatum regions. Glutathione level was not altered with CA treatment. Similar observation was made with dextromethorphan. The general behavior, locomotor activity, and CAl a region of the hippocampus was significantly protected by CA indicating neuroprotective effect of CA in MSG induced excitotoxic condition. Hence it can be concluded that CA protected MSG induced neurodegeneration attributed to its antioxidant and behavioural properties. The researchers concluded that this activity of Centella asiatica can be explored in epilepsy, stroke and other degenerative conditions in which the role of glutamate is known to play vital role in the pathogenesis.23
  • Vascular effects: A controlled study in 21 subjects with postphlebitic limbs or lymphedema reports that daily Centellase (TTFCA) causes a significant decrease in both the lymphatic/plasma protein concentration ratio and distal edema.24 The total triterpenic fraction of Centella asiatica (TTFCA) has been noted to reduce ankle edema, foot swelling, and capillary filtration rate, as well as to improve microcirulatory parameters (including resting flux, venoarteriolar response, PO2, PCO2) in subjects with reported venous insufficiency of the lower extremities.25 HU300 (containing 17.5mg of total triterpenoids derived from Centella asiatica), two tablets twice daily, is reported to decrease venous distensibility index, reduce venous congestion, and reduce supine venous pressure after eight months in subjects with venous insufficiency, deep vein thrombosis, or perimalleolar leg ulcers.26
  • Wound/burn healing effects: Asiatic acid, madecassic acid, and asiaticoside have been shown to stimulate the in vitro synthesis of collagen, both alone and in combination.27 The titrated extract of Centella asiatica (TECA), asiatic acid, and asiaticoside were shown to increase remodeling of a wound collagen matrix after injection into an animal model, through the stimulation of both collagen and glycosaminoglycan synthesis.28 Asiaticoside isolated from Centella asiatica increased hydroxyproline content, tensile strength, and collagen content of wounds after topical administration in an animal model.29,30 Asiaticoside was found to promote angiogenesis in chick chorioallantoic membranes in vitro.29,30 The application of topical 0.2% asiaticoside twice daily for seven days to cutaneous wounds in rats led to increased wound levels of antioxidants (superoxide dismutase, catalase, glutathione peroxidase, vitamin E, and ascorbic acid) and decreased lipid peroxide levels.29,30 Increased cellular proliferation and collagen synthesis was observed at wound sites after treatment with topical or oral extract of Centella asiatica in rats.8 An animal study found that application of topical Centella asiatica extract three times daily for 24 days to open wounds resulted in increased collagen content and tensile strength.31 An in vitro study of the effects of total triterpenoid fraction of Centella asiatica (TTFCA) on human skin fibroblasts found the extract to have no significant effect on cell proliferation, total protein synthesis, or proteoglycan synthesis; however, a significant increase in the percentage of collagen and cell layer fibronectin was observed.32 Asiaticoside was found to cause a dose-related increase in tensile strength after intramuscular administration of asiaticoside.10
  • Madecassol, an asiaticoside containing compound, inhibited the biosynthesis of acid mucopolysaccharides and collagens in an animal granuloma model.9 Madecassol also inhibited the proliferation of human embryo fibroblasts in vitro.9

Pharmacodynamics/Kinetics:

  • Absorption: An animal study found that madecassoside, asiaticoside, Asiatic acid, and madecassic acid have a bioavailability between 30 and 50%.33
  • Distribution: Bosse et al. reported that peak plasma levels are reached 2-4 hours after oral ingestion, intramuscular injection, or topical application of Madecassol, a gotu kola preparation.3 Grimaldi et al. also found no difference in time to peak plasma concentration with different dosages or single versus chronic dosing in a crossover study of the total triterpenic fraction of Centella asiatica (TTFCA).34 The area under the curve significantly increased in a dose-dependent fashion after single doses of either 30mg or 60mg TTFCA in humans.34
  • After chronic treatment for seven days with either 30mg or 60mg TTFCA twice daily, it was observed that peak plasma concentrations, AUC0-24, and half-life were significantly higher than after single dose administration, possibly explained by the fact that asiaticoside is transformed into asiatic acid in vivo.34
  • Metabolism: A study in 12 healthy volunteers found that asiaticoside is converted to asiatic acid in vivo by hydrolytic cleavage of the sugar moiety.35
  • Elimination: Madecassol is predominantly eliminated in the feces within 24-76 hours after ingestion, injection, or application, with a small unspecified amount metabolized by the kidneys.3

References

  1. Mook-Jung, I., Shin, J. E., Yun, S. H., Huh, K., Koh, J. Y., Park, H. K., Jew, S. S., and Jung, M. W. Protective effects of asiaticoside derivatives against beta-amyloid neurotoxicity. J Neurosci Res 11-1-1999;58(3):417-425. 10518115
  2. Dutta, T. and Basu, U. P. Crude extract of Centella asiatica and products derived from its glycosides as oral antifertility agents. Indian J Exp Biol 1968;6(3):181-182. 5718539
  3. Bosse, J. P., Papillon, J., Frenette, G., Dansereau, J., Cadotte, M., and Le Lorier, J. Clinical study of a new antikeloid agent. Ann Plast Surg 1979;3(1):13-21. 396846
  4. Babu, T. D., Kuttan, G., and Padikkala, J. Cytotoxic and anti-tumour properties of certain taxa of Umbelliferae with special reference to Centella asiatica (L.) Urban. J Ethnopharmacol 8-11-1995;48(1):53-57. 8569247
  5. Chatterjee, T. K., Chakraborty, A., Pathak, M., and Sengupta, G. C. Effects of plant extract Centella asiatica (Linn.) on cold restraint stress ulcer in rats. Indian J Exp Biol 1992;30(10):889-891. 1293014
  6. Ji B, Chen B, Jia B, and et al. Effect of titrated extract of Centella asiatica on experimental gastric injury - the mechanism of initial investigation [published abstract]. Journal of Gastroenterology & Hepatology 1997;12(Supplement A214):A214.
  7. Sairam, K., Rao, C. V., and Goel, R. K. Effect of Centella asiatica Linn on physical and chemical factors induced gastric ulceration and secretion in rats. Indian J Exp Biol 2001;39(2):137-142. 11480209
  8. Suguna, L., Sivakumar, P., and Chandrakasan, G. Effects of Centella asiatica extract on dermal wound healing in rats. Indian J Exp Biol 1996;34(12):1208-1211. 9246912
  9. Sasaki, S., Shinkai, H., Akashi, Y., and Kishihara, Y. Studies on the mechanism of action of asiaticoside (Madecassol) on experimental granulation tissue and cultured fibroblasts and its clinical application in systemic scleroderma. Acta Derm Venereol 1972;52(2):141-150. 4127803
  10. Velasco, M. and Romero, E. Drug interaction between asiaticoside and some anti-inflammatory drugs in wound healing of the rat. Curr Ther Res Clin Exp 1976;19(1):121-125. 812656
  11. Bradwejn J, Zhou Y, Koszycki, and et al. Effect of acute administration of Gotu-kola (Centella asiatica) on acoustic startle response in healthy volunteers. XXIst Collegium Internationale Neuro-psychopharmacologicum, Glascow, Scotland (July 12-16) 1998;(Abstract Ref: NRW001)
  12. Bradwejn J, Koszycki D, Shlik J, and et al. Centella asiatica decreases the acoustic startle response. 152nd Annual Meeting of the American Psychiatric Association, Washington DC, USA (May 15-20) 1999;
  13. Bradwejn, J., Zhou, Y., Koszycki, D., and Shlik, J. A double-blind, placebo-controlled study on the effects of Gotu Kola (Centella asiatica) on acoustic startle response in healthy subjects. J Clin Psychopharmacol 2000;20(6):680-684. 11106141
  14. Chen, Y. J., Dai, Y. S., Chen, B. F., Chang, A., Chen, H. C., Lin, Y. C., Chang, K. H., Lai, Y. L., Chung, C. H., and Lai, Y. J. The effect of tetrandrine and extracts of Centella asiatica on acute radiation dermatitis in rats. Biol Pharm Bull 1999;22(7):703-706. 10443466
  15. Jorge, O. A. and Jorge, A. D. Hepatotoxicity associated with the ingestion of Centella asiatica. Rev Esp Enferm Dig 2005;97(2):115-124. 15801887
  16. Kaziulin, A. N., Petukhov, A. B., and Kucheriavyi, IuA. [Efficiency of includes of bioactive substances in diet of patient with hepatic encephalopathy]. Vopr Pitan 2006;75(2):40-44. 16729760
  17. Herbert, D., Paramasivan, C. N., Prabhakar, R., and Swaminathan, G. In vitro experiments with Centella asiatica: investigation to elucidate the effect of an indigenously prepared powder of this plant on the acid- fastness and viability of M. tuberculosis. Indian J Lepr 1994;66(1):65-68. 7983394
  18. Medda, S., Das, N., Mahato, S. B., Mahadevan, P. R., and Basu, M. K. Glycoside-bearing liposomal delivery systems against macrophage- associated disorders involving Mycobacterium leprae and Mycobacterium tuberculosis. Indian J Biochem Biophys 1995;32(3):147-151. 7590855
  19. Yoosook, C., Bunyapraphatsara, N., Boonyakiat, Y., and Kantasuk, C. Anti-herpes simplex virus activities of crude water extracts of Thai medicinal plants. Phytomedicine 2000;6(6):411-419. 10715843
  20. Zheng, M. S. An experimental study of the anti-HSV-II action of 500 herbal drugs. J Tradit Chin Med 1989;9(2):113-116. 2550706
  21. Brinkhaus, B., Lindner, M., Schuppan, D., and Hahn, E. G. Chemical, pharmacological and clinical profile of the East Asian medical plant Centella asiatica. Phytomedicine 2000;7(5):427-448. 11081995
  22. Cesarone MR, Belcaro G, Nicolaides AN, and et al. Increase in echogenicity of echolucent carotid plaques after treatment with total triterpenic fraction of Centella asiatica: a prospective, placebo-controlled, randomized trial. Angiology 2001;52(10 suppl 2):S19-S25.
  23. Ramanathan, M., Sivakumar, S., Anandvijayakumar, P. R., Saravanababu, C., and Pandian, P. R. Neuroprotective evaluation of standardized extract of Centella asciatica in monosodium glutamate treated rats. Indian J Exp Biol 2007;45(5):425-431. 17569283
  24. Cesarone MR, Laurora G, Pomante P, and et al. [Efficacy of TTFCA in reducing the ratio between lymphatic and plasma protein concentration in lymphatic and postphlebetic edema]. Minerva Cardioangiol 1991;39(12):475-478.
  25. Cesarone, M. R., Laurora, G., De Sanctis, M. T., and Belcaro, G. [Activity of Centella asiatica in venous insufficiency]. Minerva Cardioangiol 1992;40(4):137-143. 1528498
  26. Mahajani SS, Oberai C, Jerajani H, and et al. Study of the venodynamic effect of an Ayurvedic formulation of Centella asiatica using venous occlusion plethysmography (VOP) and laser-Doppler velocimetry (LVD). Can J Physiol Pharmacol 1994;72(supplement 1):180.
  27. Bonte, F., Dumas, M., Chaudagne, C., and Meybeck, A. Influence of asiatic acid, madecassic acid, and asiaticoside on human collagen I synthesis. Planta Med 1994;60(2):133-135. 8202564
  28. Maquart, F. X., Chastang, F., Simeon, A., Birembaut, P., Gillery, P., and Wegrowski, Y. Triterpenes from Centella asiatica stimulate extracellular matrix accumulation in rat experimental wounds. Eur J Dermatol 1999;9(4):289-296. 10356407
  29. Shukla, A., Rasik, A. M., Jain, G. K., Shankar, R., Kulshrestha, D. K., and Dhawan, B. N. In vitro and in vivo wound healing activity of asiaticoside isolated from Centella asiatica. J Ethnopharmacol 1999;65(1):1-11. 10350364
  30. Shukla, A., Rasik, A. M., and Dhawan, B. N. Asiaticoside-induced elevation of antioxidant levels in healing wounds. Phytother Res 1999;13(1):50-54. 10189951
  31. Sunilkumar, Parameshwaraiah, S., and Shivakumar, H. G. Evaluation of topical formulations of aqueous extract of Centella asiatica on open wounds in rats. Indian J Exp Biol 1998;36(6):569-572. 9731470
  32. Tenni, R., Zanaboni, G., De Agostini, M. P., Rossi, A., Bendotti, C., and Cetta, G. Effect of the triterpenoid fraction of Centella asiatica on macromolecules of the connective matrix in human skin fibroblast cultures. Ital J Biochem 1988;37(2):69-77. 3042688
  33. Vogel HG, DeSouza N, and D'Sa A. Effects of terpenoids isolated from Centella asiatica on granuloma tissue. Acta Therapeutica 1990;16:285-298.
  34. Grimaldi, R., De Ponti, F., D'Angelo, L., Caravaggi, M., Guidi, G., Lecchini, S., Frigo, G. M., and Crema, A. Pharmacokinetics of the total triterpenic fraction of Centella asiatica after single and multiple administrations to healthy volunteers. A new assay for asiatic acid. J Ethnopharmacol 1990;28(2):235-241. 2329813
  35. Rush, W. R., Murray, G. R., and Graham, D. J. The comparative steady-state bioavailability of the active ingredients of Madecassol. Eur J Drug Metab Pharmacokinet 1993;18(4):323-326. 8020529




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