Sinomenine ameliorates fibroblast-like synoviocytes dysfunction by promoting phosphorylation and nuclear translocation of CRMP2.

ETHNOPHARMACOLOGICAL RELEVANCE: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and arthritic pain. Sinomenine (SIN), derived from the rhizome of Chinese medical herb Qing Teng (scientific name: Sinomenium acutum (Thunb.) Rehd. Et Wils), has a longstanding use in Chinese traditional medicine for treating rheumatoid arthritis. It has been shown to possess anti-inflammatory, analgesic, and immunosuppressive effects with minimal side-effects clinically. However, the mechanisms governing its effects in treatment of joint pathology, especially on fibroblast-like synoviocytes (FLSs) dysfunction, and arthritic pain remains unclear. AIM: This study aimed to investigate the effect and underlying mechanism of SIN on arthritic joint inflammation and joint FLSs dysfunctions. MATERIALS AND METHODS: Collagen-induced arthritis (CIA) was induced in rats and the therapeutic effects of SIN on joint pathology were evaluated histopathologically. Next, we conducted a series of experiments using LPS-induced FLSs, which were divided into five groups (Naïve, LPS, SIN 10, 20, 50 µg/ml). The expression of inflammatory factors was measured by qPCR and ELISA. The invasive ability of cells was detected by modified Transwell assay and qPCR. Transwell migration and cell scratch assays were used to assess the migration ability of cells. The distribution and content of relevant proteins were observed by immunofluorescence and laser confocal microscopy, as well as Western Blot and qPCR. FLSs were transfected with plasmids (CRMP2 T514A/D) to directly modulate the post-translational modification of CRMP2 protein and downstream effects on FLSs function was monitored. RESULTS: SIN alleviated joint inflammation in rats with CIA, as evidenced by improvement of synovial hyperplasia, inflammatory cell infiltration and cartilage damage, as well as inhibition of pro-inflammatory cytokines release from FLSs induced by LPS. In vitro studies revealed a concentration-dependent suppression of SIN on the invasion and migration of FLSs induced by LPS. In addition, SIN downregulated the expression of cellular CRMP2 that was induced by LPS in FLSs, but increased its phosphorylation at residue T514. Moreover, regulation of pCRMP2 T514 by plasmids transfection (CRMP2 T514A/D) significantly influenced the migration and invasion of FLSs. Finally, SIN promoted nuclear translocation of pCRMP2 T514 in FLSs. CONCLUSIONS: SIN may exert its anti-inflammatory and analgesic effects by modulating CRMP2 T514 phosphorylation and its nuclear translocation of FLSs, inhibiting pro-inflammatory cytokine release, and suppressing abnormal invasion and migration. Phosphorylation of CRMP2 at the T514 site in FLSs may present a new therapeutic target for treating inflammatory joint's destruction and arthritic pain in RA.

Sinomenine regulates immune cell subsets: Potential neuro-immune intervene for precise treatment of chronic pain.

Chronic pain is a disease of long-lasting pain with unpleasant feelings mediated by central and (or) peripheral sensitization, its duration usually lasts more than 3 months or longer than the expected recovery time. The patients with chronic pain are manifested with enhanced sensitivity to noxious and non-noxious stimuli. Due to an incomplete understanding of the mechanisms, patients are commonly insensitive to the treatment of first line analgesic medicine in clinic. Thus, the exploration of non-opioid-dependent analgesia are needed. Recent studies have shown that "sinomenine," the main active ingredient in the natural plant "sinomenium acutum (Thunb.) Rehd. Et Wils," has a powerful inhibitory effect on chronic pain, but its underlying mechanism still needs to be further elucidated. A growing number of studies have shown that various immune cells such as T cells, B cells, macrophages, astrocytes and microglia, accompanied with the relative inflammatory factors and neuropeptides, are involved in the pathogenesis of chronic pain. Notably, the interaction of the immune system and sensory neurons is essential for the development of central and (or) peripheral sensitization, as well as the progression and maintenance of chronic pain. Based on the effects of sinomenine on immune cells and their subsets, this review mainly focused on describing the potential analgesic effects of sinomenine, with rationality of regulating the neuroimmune interaction.