LAUSR

&NA; Diosgenin, a precursor of steroid hormones in plants, is known to exhibit diverse pharmacological activities including anti‐inflammatory properties. In this study, (3&bgr;, 25R)‐spirost‐5‐en‐3‐oxyl (2‐((2((2‐aminoethyl)amino)ethyl)amino)ethyl) carbamate (DGP), a new synthetic diosgenin derivative incorporating primary amine was used to investigate its anti‐inflammatory effects and underlying mechanisms of action in lipopolysaccharide (LPS)‐stimulated microglial BV2 cells. Pretreatment with DGP resulted in significant inhibition of nitric oxide (NO) synthesis, and down‐regulation of nitric oxide synthase (iNOS) and cyclooxygenase‐2 (COX‐2) in LPS‐stimulated microglial BV2 cells. In addition, DGP decreased the production of reactive oxygen species (ROS) and pro‐inflammatory cytokines such as interleukin (IL)‐6, IL‐1&bgr;, and tumor necrosis factor alpha (TNF‐&agr;). The inhibitory effects of DGP on these inflammatory mediators in LPS‐stimulated microglial BV2 cells were regulated by NF‐&kgr;B signaling through blocking p65 nuclear translocation and NF‐&kgr;B p65/DNA binding activity. DGP also blocked the phosphorylation of c‐Jun amino‐terminal kinase (JNK), but not p38 kinase or extracellular signal‐regulated kinases (ERK). The NF‐&kgr;B inhibitor JSH‐23 and JNK‐specific inhibitor SP600125 significantly decreased NO production and IL‐6 release in LPS‐stimulated BV2 cells, respectively. The overall results demonstrate that DGP has anti‐inflammatory effects on LPS‐stimulated BV2 cells via inhibition of NF‐&kgr;B and JNK activation, suggesting that DGP is a potential prophylactic agent in various neurodegenerative disorders. Graphical abstract: Figure. No caption available. HighlightsA new synthetic diosgenin derivative incorporating primary amine (DGP) was prepared.DGP suppresses LPS‐stimulated inflammatory responses in microglial BV2 cells.DGP exerts anti‐inflammatory effect via inhibition of NF‐&kgr;B and JNK MAPK signaling.DGP has potential to prevent various neurodegenerative disorders as a therapeutic agent.