## 6 Therapeutic Actions of Madecassoside and Other Major Compounds in _C. asiatica_
### Neurodegenerative Diseases
Neurite formation is considered to be one of the essential steps in neuro-regeneration, particularly for memory enhancement [113]. The pentacyclic triterpeniod madecassoside, asiaticoside, madecassic acid and asiatic acid are among various natural products that exhibited positive neuroactivity. Immunofluorescent staining studies using the cell line neuro2\(\alpha\) showed madecassoside and asiaticoside to produce a significant elevation in the percentage of neurite-bearing cells and in neurite length; madecassoside and asiaticoside were more potent than madecassic acid and asiatic acid. The activity of the glycosides in promoting neurite outgrowth required sustained activation of ERK1/2 leading to CREB phosphorylation, while neurite lengthening required activation of protein kinase B (Akt) [113]. Neuroinflammation is not only involved in neurodegenerative diseases, but also implicated as a key player in the pathology of cerebral ischemia-reperfusion (I/R) injury [141]. Madecassoside significantly reduced the brain infarct area, resolved the neurological deficit and ameliorated neuronal apoptosis in rats subjected to cerebral I/R. Furthermore, it substantially diminished the MDA and NO levels and heightened antioxidant activity in these animals, as well as decreased the levels of pro-inflammatory cytokines and of NF-\(\kappa\)B p65 [141]. In an in vitro ischemic model of oxygen-glucose deprivation followed by reperfusion (OGD/R) in BV2 microglia, madecassoside not only significantly rescued OGD/R-induced cytotoxicity, but also suppressed the secretion of pro-inflammatory cytokines, such as TNF-\(\alpha\), IL-1\(\beta\) and IL6. This study concluded that the significant neuroprotective effect of madecassoside against I/R injury both in vivo and in vitro was produced by the attenuation of microglia-mediated neuroinflammation through inhibition of the TLR4/MyD88/NF-\(\kappa\)B signaling pathway [142]. In an in vitro ischemia-hypoxia model asiaticoside increased the neuronal survival rate in a concentration-dependent manner, modulating the expression of apoptotic factors such as Bcl-2, Bax and caspase-3 [143]. Asiaticoside also had a neuroprotective effect against transient cerebral ischemia and reperfusion in a mouse model, by reducing microglial activation, iNOS activity and the level of NO. It also reduced the gene expression of inflammatory cytokines, such as TNF-\(\alpha\), IL-1\(\beta\) and IL6 by inhibiting the p38 MAPK signaling pathway [144]. Asiatic acid attenuated cerebral infarction, mitochondrial dysfunction and the induction and activation of matrix metalloproteinase-9 produced by middle cerebral artery occlusion in the rat [51]; similarly, it reduced infarct size, and improved neurological outcome in a mouse model of focal cerebral ischemia, these effects being accompanied by a reduction in BBB permeability [145]. As neuroinflammation is a major factor underlying neurodegenerative diseases, attenuating neuroinflammation is an important target of any therapy [111]. In a model of neuroinflammation induced by lipopolysaccharideacharide (LPS), which triggers toll-like receptor 4 activation on the microglia surface, madecassoside markedly reduced the production of ROS, while also concentration-dependently downregulating the gene and protein expression of pro-inflammatory components such as iNOS, COX-2, STAT1 and NF-\(\kappa\)B, and increasing the anti-neuroinflammatory heme oxygenase 1 [111]. Likewise, asiatic acid protected against methamphetamine-stimulated neuroinflammation and neurotoxicity via inhibition of NF-\(\kappa\)B/STAT3/ERK and mitochondria-mediated apoptosis pathway [146]. Mass accumulation of the endogenous neurotoxin quinolinic acid (QA) causes excessive oxidative stress that leads to neuroinflammation. Treatment with asiatic acid prevented quinolinic acid-induced spatial memory loss and alleviated oxidative stress; these effects were accompanied by improved antioxidant status and a reduction in the dysfunction in mitochondrial oxidative phosphorylation [147].