Dihydromyricetin (DHM) Inhibits Microglial Pyroptosis and Oxidative Stress After Spinal Cord Injury by Promoting STING-Mediated Autophagy.

Abstract

Dihydromyricetin (DHM) inhibits the progression of neuroinflammation-related diseases. Here, we aimed to explore the effect of DHM on spinal cord injury (SCI). First, an SCI mouse model was established by external force injury and treated with DHM (150 mg/kg) by gavage for 28 days. The results showed that DHM alleviated neuronal injury and improved motor dysfunction in SCI mice. Moreover, DHM decreased the levels of pyroptosis-related proteins, such as IL-18, NLRP3, ASC, GSDMD, and Caspase-1, and upregulated the levels of oxidative stress-related proteins, such as SOD1 and HO-1, in SCI mice. Interestingly, DHM inhibited the stimulator of interferon gene (STING) protein expression in SCI mice. Next, microglia (BV-2 cells) were treated with hydrogen peroxide (H₂O₂) to construct a cell model and pretreated with 100 μM DHM for 24 h. The results showed that DHM promoted the expression of autophagy-related proteins (Beclin1, VPS34, CTSD, and LC3II), inhibited oxidative stress and pyroptosisin H₂O₂-induced BV-2 cells. 3-MA, an inhibitor of autophagy, STING overexpression vectors, and small interfering RNAs were used to reverse the effect of DHM on H₂O₂-induced microglia. 3-MA counteracted the protective effect of DHM on H₂O₂-induced BV-2 cells. Silencing STING induced autophagy and inhibited oxidative stress and pyroptosis in H₂O₂-induced BV-2 cells; overexpression of STING promoted the phosphorylation of PI3K and AKT. 740 Y-P, an activator of PI3K, reversed the effects of STING silencing on H₂O₂-induced BV-2 cells. In conclusion, DHM inhibited pyroptosis and oxidative stress by upregulating STING-mediated autophagy, thus improving motor dysfunction in SCI mice.