Research Progress on Pharmacological Effects and Mechanism of Asiaticoside

Asiaticoside is one of the main components of triterpenoid saponins, which is the centella asiatica extract, and its molecular formula is C48H78O19. Modern pharmacological research has proved that asiaticoside has good effects on anti-inflammatory, inhibiting scar formation, promoting wound healing, neuroprotection, anti-anxiety and immune regulation. 

Graph of chemical structures of asiaticoside 

1. Anti-inflammatory mechanism 

Asiaticoside can alleviate many inflammatory reactions, and its mechanism is related to down-regulating the expression of IL-6, IL-1β and TNF-α in NF-κB pathway and inhibiting oxidative stress. According to the reasearch, on the one hand, asiaticoside can play an anti-inflammatory role by inhibiting NF-κB signaling pathway and down-regulating the expression of nitric oxide (NO), TNF-α and IL-6. On the other hand, asiaticoside can also exert its anti-inflammatory effect by regulating heme oxygenase-1 (HO-1) signaling pathway and inhibiting the production of pro-inflammatory factors and the activity of peroxidase. Asiaticoside can relive the inflammatory reaction caused by hypoxia by inhibiting NF-κB/p38 signaling pathway, and it can also alleviate the inflammatory reaction induced by hyperoxia by down-regulating the expression of microRNA-155 (miR-155) and up-regulating the expression of suppressor of cytokine signaling 1 (SOCS1). 

2. Mechanism of relieving the injury of liver, lung and kidney 

Asiaticoside can relieve the injury of liver, lung and kidney, and its mechanism is related to its effects of inhibiting inflammatory reaction of oxidative stress and improving antioxidant capacity. Researches have shown that asiaticoside can relieve both sepsis-associated lung injury and acute sepsis-associated kidney injury. Asiaticoside can relieve lung injury by up-regulating the expression of PPAR-γ and inhibiting the activity of MAPK and NF-κB signaling pathway. Besides, the relieving of kidney injury can be achieved when asiaticoside down-regulates the expression of IL-6 in serum and iNOS protein in kidney tissue. Asiaticoside can relieve the kidney injury in nephropathy model rats, and its mechanism is related to up-regulating mRNA expression of synaptophysin, endorphin and podofilox, and down-regulating mRNA expression of desmin. Researches have been carried out in vivo and vitro to figure out whether the asiaticoside is effective in improving the injury of the rats. It was found that asiaticoside could relieve the lung injury in rats by reducing the contents of myeloperoxidase (MPO), malondialdehyde (MDA), the level of TNF-α, IL-1β and IL-6 and increasing the level of total antioxidant (TAOC). Additionally, asiaticoside can improve liver injury by inhibiting the expression of TNF-α and MAPK. 

3. Mechanism of inhibiting scar hypertrophy and repairing skin damage 

The mechanism of asiaticoside inhibiting scar hypertrophy and repairing skin damage is related to inhibiting the expression of type I and III collagen, TNF-α, IL-6, IL-1β and the activity of Wnt/β-catenin signaling pathway, and up-regulating the expression of TGF-β1, VEGF, iNOS and MCP-1. 

Asiaticoside can inhibit the proliferation of scar fibroblasts. When the concentration of asiaticoside is 0.1-1.0mg/ml, the proliferation of fibroblasts will be obviously inhibited, which suggests that asiaticoside can reduce the synthesis of granulation tissue and extracellular matrix, such as collagen, by inhibiting fibroblasts, thus reducing the scar formation. When the concentration of asiaticoside is 1.0mg/ml, it can inhibit the mRNA expression of type I and type III collagen in scar fibroblasts, which indicates that asiaticoside can inhibit the scar formation by reducing the production of collagen and the synthesis of extracellular matrix. The results show that asiaticoside could inhibit the collagen secretion function by inhibiting overactive fibroblasts, through which asiaticoside can inhibit the collagen proliferation and intervene the scar formation. 

In vitro researches show that the mechanism of asiaticoside inhibiting the proliferation of scar fibroblasts is related to the inhibition of the expression of proteins relating to RhoA/Rho kinase I (RhoA/ROCK I) signaling pathway, as well as the down-regulation of the expression of autocrine type I and III collagen and TGF-β1 mRNA. According to the researches, it was found that the scar area of ear-scar model rabbits gradually decreases with the increase of administration time. Its mechanism is related to the decrease of TGF-β1 expression level. Asiaticoside can inhibit the hypertrophic scar formation in domestic rabbits by down-regulating the expression of type I and III collagen, IL-1β, IL-6 and IL-8 mRNA and up-regulating the mRNA expression of Smad7, PPAR γ, which shows dose dependence. It has been found that coaxial nanofibers loaded with asiaticoside can promote the healing of deep second degree burn wounds in rats by up-regulating the expressions of VEGF, PCNA and endothelial cell adhesion molecule (CD31) and down-regulating the expressions of TNF-α and IL-6. Additionally, many other researches have revealed that asiaticoside can also promote the production of monocyte chemoattractant protein-1 (MCP-1) and promote the healing of burn wounds. 

Asiaticoside complex can alleviate the inflammatory reaction of diabetic skin ulcer (DCU) model rats, inhibit the growth of bacteria in wound, promote wound healing, and up-regulate the expression of VEGF, iNOS, endothelial nitric oxide synthase (eNOS) and CD34. Its mechanism is related to the down-regulation of Wnt/β-catenin signaling pathway. Random skin flap is a common method in burn and surgical repair, which refers to select an area similar to the damaged skin area as a skin flap according to the skin defect, and then transfer the skin flap to the defect area to repair the skin defect. It has been found that asiaticoside can increase the survival area of rat skin flap, and its mechanism is related to the up-regulation of the expression of superoxide dismutase (SOD) and VEGF and down-regulation of the expression of inflammatory factors. In other studies, it has been found that asiaticoside-sodium alginate repair patch and asiaticoside nanoemulsion prepared from asiaticoside are effective for repairing skin damage. 

4. Mechanism of anti-Alzheimer's disease 

Asiaticoside can ameliorate Alzheimer's disease (AD) by preventing HUVEC from apoptosis, inhibiting the activity of TLR4/NF-κB signaling pathway and the expression of inflammatory factors IL-1, IL-6 and TNF-α. According to literature reports, asiaticoside can alleviate neurogenic inflammation by reducing the level of NO and decresing the expression capacity of iNOS mRNA in astrocytes. Asiaticoside can improve the injury of vascular endothelial cells (HUVEC) induced by Aβ, and its mechanism is related to inhibiting cell apoptosis and the expression of IL-1, IL-6 and TNF-α. The intervention effect of asiaticoside on the apoptosis of human brain microvascular endothelial cells hBMECs induced by Aβ1-42 showed that asiaticoside could inhibit the apoptosis of hBMECs cells. Its mechanism is related to inhibiting the expression of TLR4 in TLR4/NF-κB signaling pathway, myeloid differentiation factor 88 (MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF6), the expression of p-NF-κB p65 protein and nuclear migration of NF-κB, as well as the expression of TNF-α and IL-6. Asiaticoside can regulate the production of Aβ before neuropathy, thus preventing the occurrence of AD. Asiaticoside can protect HUVEC injury caused by Aβ1-42, and its mechanism is related to up-regulating the expression of Bcl-2 and down-regulating the expression of Bax. It has been found that asiaticoside can significantly reverse AD induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), which is related to the increase of Bcl-2/Bax ratio. Moreover, asiaticoside has a strong ability to penetrate the blood-brain barrier. Therefore, it has great potential to treat neurodegenerative diseases. 

5. Anti-fibrosis mechanism 

Asiaticoside can alleviate the fibrosis of lung, liver, kidney and heart, and its mechanism is related to down-regulating the expression of TGF-β1, CTGF, ALT, asiaticoside T and Hyp. On the basis of related studies, it has been found that asiaticoside would inhibit human embryonic dermal fibroblasts and human lung fibroblasts when the mass concentration of it is 400μg/ml. The anti-fibrosis mechanism works when asiaticoside down-regulates the expression level of TGF-β1mRNA by inhibiting the production of inflammatory cytokines. Asiaticoside can significantly improve renal fibrosis in unilateral ureteral obstruction (UUO) model rats, and its mechanism is related to down-regulating the expression of connective tissue growth factor (CTGF) in renal interstitium and collagen type III (Col III). In addition, asiaticoside can also improve myocardial fibrosis after myocardial infarction in rats. Asiaticoside can alleviate the fibrosis of hepatic fibrosis in rats, and significantly reduce the levels of ALT, asiaticoside T and Hyp in rats' serum, which indicates that asiaticoside can improve the immune hepatic fibrosis. Asiaticoside can alleviate the lung fibrosis in rats caused by bleomycin (BLM), and its mechanism is related to the regulation of TGF-β1/Smad pathway. On the basis of other studies, it has been found that asiaticoside can also significantly relieve the pulmonary fibrosis of mice, and its mechanism is to ameliorate pulmonary fibrosis by activating A2AR-assisted cyclic adenosine monophosphate (cAMP)/R asiaticoside-related protein 1 (RAP1) signaling pathway. 

6. Mechanism of improving learning and memory ability 

Asiaticoside can improve the learning and memory ability of mice, and its mechanism is related to reducing the deposition of Aβ in hippocampus and up-regulating the expression of synaptophysin (SYN) protein. It is also related to up-regulating the protein expression of peroxisome proliferator-activated receptor γ (PPARγ) and down-regulating the expression of inflammatory factors IL-6, TNF-α and IL-1 expression. In the related studies, it has also been found that asiaticoside has a good preventive and therapeutic effect on diabetic cognitive dysfunction, and its mechanism is related to the regulation of oxidative stress and PI3K/Akt/NF-κB pathway. 

At present, most of the researches on the mechanism of asiaticoside are still at the prelimilary stage. However, with the wider application of many cell and molecular biology in the field of drug mechanism research, it is believed that the action mechanism of asiaticoside will become more and more clear, which will lay a firm foundation for the clinical development of new formulation and new treatment fields. 

References 

[1] Qin Huizhen, Lin Si, Deng Lingyu, Zhu Hua. Research Progress on Pharmacological Effects and Mechanism of Asiaticoside [J]. China Pharmacy, 2021, 32 (21): 2683-2688.

[2] Guo Yujie, Xu Jun. Research Progress on Pharmacological Effects of asiaticoside [J]. Shanxi Medical Journal, 2017, 46 (15): 1829-1832. 

[3] Ding Yuan, Zhang Zhu, Wang Suogang. Research Progress of Asiaticoside [J]. Lishizhen Medicine and Materia Medica Research (engaged in drug inspection and analysis and verification of analysis methods) 

About the author: Xiao Michong, a drug quality researcher, has been committed to drug quality research and drug analysis method verification for a long time, and now works in a large Chinese drug R&D company, engaging in drug inspection and analysis and verification of analysis methods.