Differential Action between Schisandrin A and Schisandrin B in Eliciting an Anti-Inflammatory Action: The Depletion of Reduced Glutathione and the Induction of an Antioxidant Response

Abstract

Schisandrin A (Sch A) and schisandrin B (Sch B) are active components of Schisandrae Fructus. We compared the biochemical mechanism underlying the anti-inflammatory action of Sch A and Sch B, using cultured lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and concanavalin (ConA)-stimulated mouse splenocytes. Pre-incubation with Sch A or Sch B produced an anti-inflammatory action in LPS-stimulated RAW264.7 cells, as evidenced by the inhibition of the pro-inflammatory c-Jun N-terminal kinases/p38 kinase/nuclear factor-κB signaling pathway as well as the suppression of various pro-inflammatory cytokines and effectors, with the extent of inhibition by Sch A being more pronounced. The greater activity of Sch A in anti-inflammatory response was associated with a greater decrease in cellular reduced glutathione (GSH) level and a greater increase in glutathione S-transferase activity than corresponding changes produced by Sch B. However, upon incubation, only Sch B resulted in the activation of the nuclear factor (erythroid-derived 2)-like factor 2 and the induction of a significant increase in the expression of thioredoxin (TRX) in RAW264.7 cells. The Sch B-induced increase in TRX expression was associated with the suppression of pro-inflammatory cytokines and effectors in LPS-stimulated macrophages. Studies in a mouse model of inflammation (carrageenan-induced paw edema) indicated that while long-term treatment with either Sch A or Sch B suppressed the extent of paw edema, only acute treatment with Sch A produced a significant degree of inhibition on the inflammatory response. Although only Sch A decreased the cellular GSH level and suppressed the release of pro-inflammatory cytokines and cell proliferation in ConA-simulated splenocytes in vitro, both Sch A and Sch B treatments, while not altering cellular GSH levels, suppressed ConA-stimulated splenocyte proliferation ex vivo. These results suggest that Sch A and Sch B may act differentially on activating GST/ depleting cellular GSH and inducing an antioxidant response involved in their anti-inflammatory actions.

Schisandrin A Inhibits the IL-1β-Induced Inflammation and Cartilage Degradation via Suppression of MAPK and NF-κB Signal Pathways in Rat Chondrocytes

“…Schisandrin A, B, and C are the main representative lignans of S. sphenanthera , many studies focus on the connections and differences between them (Leong et al, 2016; Guo et al, 2017a,b). Although Schisandrin A and Schisandrin B share the close structure, their functions and mechanism of actions had been compared and studied in various diseases (Sun et al, 2014; Guo et al, 2017a).…”

Schisandrin A suppresses lipopolysaccharide-induced inflammation and oxidative stress in RAW 264.7 macrophages by suppressing the NF-κB, MAPKs and PI3K/Akt pathways and activating Nrf2/HO-1 signaling

“…Schisandrin A has also been reported to inhibit inflammation-induced neuronal damage by decreasing the production of NO, TNF-α and IL-6 induced by LPS in microglial cells; furthermore, various signaling pathways, including the NF-κB pathway, were indicated to be involved in this process, suggesting that schisandrin A is a promising candidate for treating inflammatory neurode-generative diseases ( 27 ). Similarly, this compound exhibited anti-inflammatory activity in LPS-stimulated RAW 264.7 cells; in particular, it increased glutathione S-transferase activity and decreased glutathione levels, thereby suppressing edema; this indicates that the anti-inflammatory action of schisandrin A is closely associated with its antioxidant effect ( 28 ). Furthermore, several previous studies have reported that lignan-like substances with a structure similar to that of schisandrin A possess anti-inflammatory activities and excellent Nrf2-induction or ROS-scavenging abilities ( 29 – 34 ); however, the underlying mechanisms associated with the anti-inflammatory and antioxidant activity of schisandrin A have remained to be fully elucidated.…”

Schisandra Chinensis Lignans Suppresses the Production of Inflammatory Mediators Regulated by NF-κB, AP-1, and IRF3 in Lipopolysaccharide-Stimulated RAW264.7 Cells

“…It has been reported that the most active component of SF is the lignans, which has a wide spectrum of pharmacological activities including hepatoprotective, anti-inflammatory, anti-oxidant, and anti-tumour properties [18,19,20,21]. Previous studies reported that the dibenzocyclooctadiene lignans derivatives isolated from SF, such as Schisandrin A and Schisandrin B, have potent anti-inflammatory actions via suppressing the phosphorylation of MAPKs [22]. However, as the most effective part of SF, the mechanism underlying anti-inflammatory effect of Schisandra Chinensis lignans (SCL) remains largely unknown.…”