Madecassoside

Phytomedicine. 2009 Jun;16(6-7):538-46.

Madecassoside attenuates inflammatory response on collagen-induced arthritis in DBA/1 mice.[Pubmed: 19135346 ]

Madecassoside (MA), a triterpenoid product isolated from Centella asiatica, has been described to exhibit antioxidant and anti-inflammatory activities.
METHODS AND RESULTS:
The present study was undertaken to determine whether Madecassoside (MA) is efficacious against collagen-induced arthritis (CIA) in mice and its possible mechanisms. DBA/1J mice were immunized with bovine type II collagen and treated with MA (3, 10 and 30 mg/kg d, i.g.) from days 21 to 42 after immunization. Arthritis was evaluated by hind paw swelling, polyarthritis index, and histological examination. In vitro proliferation of spleen cells was examined using 3-[4,5-dimethylthylthiazol-2-yl]-2, 5-diphenyltetrazoliumbromide (MTT) assay. Plasma levels of cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-10 (IL-10) and the expression of prostaglandin E(2) (PGE(2)), cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in synovial tissues were also determined. The results showed that comparing with untreated CIA mice, treated with MA dose-dependently suppressed the clinical arthritis score and joints tissues pathological damage, reduced the proliferation of spleen cells, plasma levels of TNF-alpha and IL-6, synovial tissues PGE(2) production and COX-2 protein expression, however, the expression of COX-1 in synovial tissues did not change and the plasma levels of IL-10 were increased.
CONCLUSIONS:
These results suggest that MA can effectively alleviate inflammatory response on CIA, and anti-inflammatory effects of MA can be attributed, at least partially, to the inhibition of pro-inflammatory mediators, including COX-2 expression, PGE(2) production, TNF-alpha and IL-6 levels and the up-regulation anti-inflammatory molecule IL-10.

Brain Res. 2014 May 27;1565:37-47.

Neuroprotective effects of madecassoside against focal cerebral ischemia reperfusion injury in rats.[Pubmed: 24735651]

Madecassoside, a triterpenoid derivative isolated from Centella asiatica, exhibits anti-inflammatory and antioxidant activities.
METHODS AND RESULTS:
We investigated its neuroprotective effect against ischemia-reperfusion (I/R) injury in cerebral neurons in male Sprague-Dawley rats. Madecassoside (6, 12, or 24mg/kg, i.v.) was administered 1h after the start of reperfusion, and neurological deficit score and infarct volume were evaluated 24h later. Neuronal apoptosis was assessed by performing terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) staining, and pathological brain damage was estimated by performing hematoxylin and eosin staining. Serum levels of malondialdehyde, superoxide dismutase activity, reduced glutathione levels, and nitric oxide levels were also determined. mRNA and protein expression of pro-inflammatory cytokines (Interleukin-1β/6, and tumor necrosis factor-α) were measured by real-time RT-PCR and ELISA, respectively; NF-κB p65 expression was determined by western blotting. Madecassoside significantly reduced brain infarct area, resolved neurological deficit, and ameliorated neuronal apoptosis. It also significantly reduced the levels of malondialdehyde and nitric oxide, and augmented the antioxidant activity in rats subjected to cerebral I/R. Moreover, the levels of pro-inflammatory cytokines and NF-κB p65 significantly reduced after Madecassoside treatment.
CONCLUSIONS:
These results indicate that Madecassoside is neuroprotective and may be useful in reducing the damage caused by stroke.

Planta Med. 2008 Jun;74(8):809-15.

Madecassoside isolated from Centella asiatica herbs facilitates burn wound healing in mice.[Pubmed: 18484522 ]

The current study was designed to investigate the effect of Madecassoside, the major triterpene in CENTELLA ASIATICA, on burn wound healing and its possible mechanism of action.
METHODS AND RESULTS:
An oral administration of Madecassoside (6, 12, 24 mg/kg) facilitated wound closure in a time-dependent manner and reached its peak effect, nearly completely wound closure, on day 20 in the group receiving the highest dose of 24 mg/kg of Madecassoside. Further histopathological analysis revealed that Madecassoside alleviated infiltration of inflammatory cells as well as enhanced epithelisation resulting from dermal proliferation of fibroblasts. Madecassoside at higher doses (12 and 24 mg/kg) decreased nitric oxide (NO) levels and malondialdehyde (MDA) content in the burn skin tissue. However, reduced glutathione (GSH) and hydroxyproline levels were increased in the same skin tissue. In addition, Madecassoside promoted skin angiogenesis IN VIVO, correlating with our findings IN VITRO that it stimulated endothelial cell growth in a rat aortic ring assay. These data suggest that Madecassoside has significant wound-healing activity and is one of the major reasons for the use of C. ASIATICA herbs in the successful treatment of burn injury.
CONCLUSIONS:
Moreover, the results from the present study indicate that the effect of Madecassoside on wound healing may involve several mechanisms including antioxidative activity, collagen synthesis and angiogenesis.

Toxicol In Vitro. 2011 Jun;25(4):890-6.

In vitro inhibitory effects of asiaticoside and madecassoside on human cytochrome P450.[Pubmed: 21349323 ]

The inhibitory effects and types of inhibition of asiaticoside and Madecassoside on human CYPs were studied in vitro using recombinant human CYPs.
METHODS AND RESULTS:
The median inhibitory concentrations (IC50) of asiaticoside and Madecassoside were determined for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Asiaticoside inhibited CYP2C19 (IC50 = 412.68 ± 15.44 μM) and CYP3A4 (IC50=343.35 ± 29.35 μM). Madecassoside also inhibited CYP2C19 (IC50 = 539.04 ± 14.18 μM) and CYP3A4 (IC50 = 453.32 ± 39.33 μM). Asiaticoside and Madecassoside had no effect on the activities of CYP1A2, CYP2C9 and CYP2D6 and CYP2E1. Assessment of mechanism-based inhibition and the type of inhibition were performed for asiaticoside and Madecassoside with CYP2C19 and CYP3A4. These results suggested that Madecassoside is a mechanism-based inhibitor of CYP2C19 and CYP3A4. Assessment of mechanism-based inhibition by asiaticoside was limited by its low solubility. Asiaticoside exhibited non-competitive inhibition of CYP2C19 (Ki=385.24 ± 8.75 μM) and CYP3A4 (Ki = 535.93 ± 18.99 μM). Madecassoside also showed non-competitive inhibition of CYP2C19 (Ki = 109.62 ± 6.14 μM) and CYP3A4 (Ki = 456.84 ± 16.43 μM).
CONCLUSIONS:
These results suggest that asiaticoside and Madecassoside could cause drug-drug interactions via inhibition of CYP2C19 and CYP3A4. An in vivo study is needed to examine this further.

Int Immunopharmacol. 2010 Jul;10(7):723-9.

Madecassoside suppresses LPS-induced TNF-alpha production in cardiomyocytes through inhibition of ERK, p38, and NF-kappaB activity.[Pubmed: 20381648 ]

Madecassoside (MA) is a major triterpenoid component of Centella asiatica that has a wide range of biological activities, including wound-healing and antioxidative activities.
METHODS AND RESULTS:
In the present study, we evaluated the therapeutic effect of MA on rat cardiac dysfunction during sepsis induced by lipopolysaccharide (LPS), as well as the possible mechanism. Pretreatment of the neonatal rat cardiomyocytes with MA inhibited LPS-induced TNF-alpha production in a concentration-dependent manner. In addition, pretreatment of the rats with MA (20 mg/kg, i.g.) significantly inhibited the elevation of plasma TNF-alpha, delayed the fall of mean arterial blood pressure, and attenuated the tachycardia induced by LPS. We further observed that MA prevented the LPS-induced nuclear factor-kappa B (NF-kappaB) translocation from the cytoplasm into the nucleus, and inhibited the LPS-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38.
CONCLUSIONS:
These results suggest that MA inhibits LPS-stimulated TNF-alpha production through the blocking of ERK1/2, p38 and NF-kappaB pathways in cardiomyocytes. MA may have cardioprotective effects in LPS-mediated sepsis.

Pharmacol Biochem Behav. 2014 Sep;124:434-42.

Protective effect of madecassoside against cognitive impairment induced by D-galactose in mice.[Pubmed: 25106808]

This study was designed to investigate the protective effect of Madecassoside from Hydrocotyle sibthorpioides against cognitive impairment induced by D-galactose (D-gal) in mice.
METHODS AND RESULTS:
The result revealed that treatment with Madecassoside significantly reversed D-gal-induced learning and memory impairments, as measured by the Morris water-maze test. Studies on the potential mechanisms of this action showed that Madecassoside significantly reduced oxidative stress and suppress inflammatory responses via blocking NF-κB and ERK/p38 MAPK pathways. Moreover, Madecassoside markedly attenuated the content and deposition of β-amyloid peptide by inducing a decrease in the expression of amyloid protein precursor, β-site amyloid cleaving enzyme-1 and cathepsin B and an increase in the levels of neprilysin and insulin-degrading enzyme. Madecassoside significantly increased the expression of synapse plasticity-related proteins in the hippocampus, such as postsynaptic density 95, long-term potentiation, N-methyl-D-aspartic acid receptors, Ca(2+)/calmodulin-dependent protein kinase II, NMDA receptor subunit 1, protein kinase C, protein kinase A, cAMP-response element binding protein, and brain-derived neurotrophic factor. In addition, Madecassoside significantly increased the levels of acetylcholine but decreased cholinesterase activity.
CONCLUSIONS:
In conclusion, the protective effect of Madecassoside against d-gal-induced cognitive impairment was mainly due to its ability to reduce oxidative damage, improve synaptic plasticity and restore cholinergic function. These findings suggest that Madecassoside can be considered as a potential agent for preventing cognitive impairment.

Biol Pharm Bull. 2008 Mar;31(3):458-63.

Madecassoside reduces ischemia-reperfusion injury on regional ischemia induced heart infarction in rat.[Pubmed: 18310910]

Madecassoside (MA), one of the principle terpenoids in Centella asiatica, has shown protect effect on isolated rat hearts and isolated cardiomyocytes against reperfusion injury in our previous studies. The aim of this study is to investigate if MA also protected against myocardial ischemia-reperfusion injury in vivo.
METHODS AND RESULTS:
The ischemia infarction model was established in rats. Left ventricular function was monitored during the ischemia-reperfusion period by a multi-channel recorder. After the ischemia-reperfusion process the infarcted areas were assessed. The levels of lactate dehydrogenase (LDH), creatinephosphokinase (CK), malondialdehyde (MDA), super-oxide dismutase (SOD) and C-reactive protein (CRP) in serum were determined. Cardiomyocytic apoptosis was measured by terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining. Pre-treatment with MA (50, 10 mg/kg) attenuated myocardial damage characteristic of decreasing infarct size, decreasing LDH and CK release. Activities of SOD were increased and MDA level increased obviously in control group whereas pretreatment with MA blunted the decrease of SOD activity, markedly reduced the level of MDA and the activity of CRP, and relieved myocardial cell apoptosis.
CONCLUSIONS:
These results suggest that MA has the protective effect on myocardial ischemia-reperfusion injury. This protection ability possibly due to its anti-lipid peroxidation, anti-inflammation and anti-apoptosis function and the enhancement of SOD activity.