## 6 Therapeutic Actions of Madecassoside and Other Major Compounds in _C. asiatica_
### Rheumatoid Arthritis  
Rheumatoid arthritis (RA) is a systemic disease distinguished by chronic inflammation, synovial hyperplasia with concomitant joint destruction, deformity and loss of function [101]. Collagen II (CII) is the core constituent protein of the cartilage in the diarthrodial joint, which is the principal site affected in RA [102]. The presence of heterologous CII species in the articular cartilage of joints initiates an immune response and Type II collagen-induced arthritis (CIA) is a well-established in vivo model for assessing the effects of anti-inflammatory or anti-rheumatic drugs, as it expresses similar immunological and pathological traits to human RA [103]. Oral administration of madecassoside to mice with CIA produced a dose-dependent reduction in paw inflammatory swelling and erythema, but did not modify the disease-associated body weight loss. Moreover, it also radically ameliorated the pathological indicators, including infiltration of inflammatory cells into the joint cavity, synovial hyperplasia, pannus formation and erosion of bone and cartilage [104]. It was hypothesized that mac accessoside downregulated the abnormal humoral and cellular immunity, such as the overproduction of auto-antibodies and the excessive activation of T lymphocytes as well as joint destruction [104]. Another study suggested that the anti-inflammatory effect of mac accessoside in mice with CIA may be associated with the inhibition of the production of TNF-\(\alpha\), IL-6, PGE\({}_{2}\) and the expression of COX-2, as well as the upregulation of the expression of the anti-inflammatory cytokine IL-10 [105]. Systemic levels of IL-10 were shown to be increased in rats with CIA receiving mac accessoside, although the secretion of IL-10 from peripheral mononuclear cells was not enhanced [106]. Furthermore, mac accessoside treatment led to a prominent increase in Foxp3+ lymphocytes in the intestinal lamina propria, one of the major sources of IL-10. This study suggested that the anti-arthritic effects of mac accessoside in rats were mediated primarily through intensifying the secretion of IL-10 from Foxp3+ lymphocytes in the intestinal lamina propria and the mobilization of IL-10 to the circulation, rather than by a systemic anti-inflammatory action [106].  
Cytokines are acknowledged to stimulate fibroblast-like synovocytes (FLS) to produce MMPs, which damage the collagen component of cartilage and bone, contributing to the joint deformity and pain in RA patients [107]. MMP-13 is one of the most important collagenases responsible for damaging the articular cartilage and is often found in higher levels in the synovial fluids of RA patients [108]. The chief inducer of MMP-13 is IL-18, mainly through pathways involving NF-kB [109]. Madecassoside reversed the histological lesions in adjuvant-induced arthritis rats and suppressed IL-18-induced invasion and migration of FLS, as well as inhibited the expression of MMP-13 in FLS but with little effect on the expression of other MMPs. Additionally, mac accessoside attenuated IL-18-stimulated p65 phosphorylation and translocation. These data suggested that mac accessoside inhibited MMP-13 by preventing NF-kB translocation and phosphorylation [110].  
As described earlier, the pharmacokinetics of mac accessoside may be influenced by the presence of arthritis. Thus, the metabolism of mac accessoside and the absorption of its metabolite mac accessic acid were amplified in rats with CIA. This may be related to arthritis-induced changes in the levels of inflammatory cytokines, the activity of intestinal bacteria and the expression of hepatic drug metabolizing enzymes [58]. No studies appear to have been reported on the anti-arthritic effects of asiaticoside, asiatic acid and mac accessic acid.