Abstract
Sinomenine has long been used for the treatment of rheumatoid arthritis in China. However, its anti-inflammatory mechanism is still debatable because the in vitro minimal effective concentration (≥250 μM) is hardly reached in either synovium or serum after oral administration at a therapeutic dose. Recent findings suggest that the α7 nicotinic acetylcholine receptor (α7nAChR) might mediate the inhibitory effect of sinomenine on macrophage activation, which attracts us to explore the anti-arthritis mechanism of sinomenine by taking neuroendocrine-inflammation axis into consideration. Here, we showed that orally administered sinomenine ameliorated the systemic inflammation of collagen-induced arthritis (CIA) rats, which was significantly diminished by either vagotomy or the antagonists of nicotinic acetylcholine receptors (especially the antagonist of α7nAChR), but not by the antagonists of muscarinic receptor. Sinomenine might bind to α7nAChR through interacting with the residues Tyr184 and Tyr191 in the pocket. In addition, the generation of vasoactive intestinal polypeptide (VIP) from the gut of CIA rats and cultured neuron-like cells was selectively enhanced by sinomenine through the activation of α7nAChR-PI3K/Akt/mTOR pathway. The elevated levels of VIP in the serum and small intestine of rats were negatively correlated with the scores of joint destruction. The crucial role of VIP in the anti-arthritic effect of sinomenine was confirmed by using VIP hybrid, a non-specific antagonist of VIP receptor. Taken together, intestine-sourced VIP mediates the anti-arthritic effect of sinomenine, which is generated by the activation of α7nAChR.
Highlights
Rheumatoid arthritis, one of the most prevalent chronic inflammatory joint diseases, can cause cartilage/bone damage and disability, and has developed to be a substantial burden for both the individuals and the society (Smolen et al, 2016)
Rapamycin (10 nM) notably abolished the phosphorylation of RPS6 induced by SIN and NIC (Figures 6C–E). These results demonstrated that both SIN and NIC induced the expression of vasoactive intestinal polypeptide (VIP) via PI3K/Akt/mTOR signaling pathway
The results showed that VIP hybrid itself did not affect the pathological features and the serum levels of pro-inflammatory cytokines in collagen-induced arthritis (CIA) rats, but it markedly attenuated the anti-arthritic effect of SIN in views of paw swelling, AI scores and histopathological scores (Figures 7A–C), as well as the serum levels of proinflammatory cytokines (TNF-α and IL-6) (Figure 7D)
Summary
Rheumatoid arthritis, one of the most prevalent chronic inflammatory joint diseases, can cause cartilage/bone damage and disability, and has developed to be a substantial burden for both the individuals and the society (Smolen et al, 2016). Several research groups attempted to illustrate the anti-arthritic mechanisms of SIN by in vitro studies, and showed that SIN could suppress osteoclast formation and fibroblast-like synoviocyte activation at concentrations over 250 μM (Chen et al, 2011; Li et al, 2013). Our recent pharmacokinetics study demonstrated that oral administration of SIN (120 mg/kg) for consecutive 14 days showed a relative lower plasma concentration in CIA rats. The plasma concentration in CIA rats peaked at only about 9 μM (Tong et al, 2015). With regard to the pharmacokinetics– pharmacodynamics disconnection, we offered a point that the anti-arthritic effect of oral SIN might be gut-dependent (Tong et al, 2016), and the precise mechanism needs to be identified
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