## 6 Therapeutic Actions of Madecassoside and Other Major Compounds in _C. asiatica_
### Neurodegenerative Diseases
Moreover, asiaticoside attenuated A\(\beta_{1-42}\)-induced cytotoxicity and apoptosis, restored declined mitochondrial membrane potential and significantly downregulated TNF-\(\alpha\), IL-6, TLR4, MyD88 and TRAF6 expressions in human brain microvascular endothelial cells (hBMECs) [118]. Administration of asiaticoside to senescence-accelerated mice (SAMP) averted spatial learning and decline by scavenging free radicals, increasing antioxidant enzymes activities, reducing A\(\beta\) load, ameliorating synaptic plasticity dysfunction and keeping ACh levels and AChE activity in check [119]. Furthermore, asiaticoside effectively protected HUVECs against impairment elicited by aggregated A\(\beta_{1-42}\), by promoting cell proliferation, apoptosis inhibition and the elevation of the Bcl-2/Bax ratio [120]. An in silico study deduced that asiaticoside hinders early phases of fibrillogenesis via interactions with nucleating amyloid species and slowing the growth phase [121]. Unlike madecassoside and asiaticoside, asiatic acid can cross the BBB to exert rapid neuroprotective actions. Administration of asiatic acid reduced aluminum-stimulated cell death by diminishing mitochondrial dysfunction, oxidative stress and signaling pathways [122] in in vitro and in vivo AD models, moderating the aluminum load, AChE activity, behavioral performance, A\(\beta\) levels and neuroinflammation [123]. Furthermore, asiatic acid exerted a neuroprotective effect against AlCl\({}_{3}\)-induced cognitive impairments, oxidative stress, cholinergic deficits, tau pathology, A\(\beta\) burden, neuroinflammation and apoptosis [124]. Asiatic acid also demonstrated protective effects against A\(\beta_{25-35}\)-induced tau protein hyperphosphorylation [125], C\({}_{2}\)-ceramide-induced neuronal cell injury [126], cholesterol-induced cytotoxicity [127], in addition to positively moderating various targets related to A\(\beta\) pathways, thus, mitigating A\(\beta\) levels in AD brain by diminishing A\(\beta\) production and escalating A\(\beta\) degradation [128]. Asiatic acid treatment also showed protection against apoptosis, oxidative and glycative stress by reducing ROS and AGE, and downregulating the expression of Bax, NADPH oxidase, RAGE and MAPK [53]. Furthermore, asiatic acid intake was shown to be effective in enhancing memory and learning, as measured by the passive avoidance test [129]; it increased cell pro liferation in the hippocampus and stimulated spatial working memory [130; 131], as well as prevented impairment of neurogenesis and spatial memory caused by valpro acid [132]. The neuroprotective effects of madecassoside have also been investigated in a rat model of early-phase Parkinsonism, comprising the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropropylidine (MPTP), a potent neurotoxin that is known to cause dopaminergic neurodegeneration by producing free radicals, leading to oxidative stress. In this model, madecassoside reduced locomotor dysfunction and preserved dopaminergic neurons. Furthermore, madecassoside markedly attenuated the MTPP-induced reduction of striatal dopamine. The MDA content was significantly reduced, while GSH levels, Bcl-2/Bax ratio and expression of BDNF protein were substantially increased in madecassoside-treated groups. These results implied that madecassoside is effective in reducing the early signs of MTPP-induced Parkinsonism [133]. Similar findings were observed in the neuroprotective effect of asiatic acid and asiaticoside against MTPP-induced neurotoxicity [54; 134; 135; 136]. In a rotenone-induced Parkinson model, asiatic acid protected against mitochondrial injury [137; 138] and exerted antiapoptotic effects through a reduction in oxidative stress, maintenance of mitochondrial membrane potential and regulation of expressions of Bcl-2, Bax and caspases [139]. Additionally, the anti-Parkinson effect of asiaticoside was accompanied by an increased expression of proteins involved in phosphoinositide signaling [140].