Cordycepin Attenuates LPS-induced Inflammation via Regulating TLR4 Signaling Pathway in BV2 Microglia Cells

Excessive neuroinflammation caused by activated microglia contributes to the progression of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Microglia, the immune cells of the central nervous system, play vital roles in brain development, immune defense, and maintaining the neural environment. Cordycepin from Cordyceps militaris exhibits diverse biological activities, including anti-inflammatory, antioxidant, and hypoglycemic effects. This study investigated the effects of ethanol extract of C. militaris fermented from Gryllus bimaculatus (EECM) and cordycepin on lipopolysaccharide (LPS)−induced neuroinflammation in BV2 microglial cells. EECM significantly reduced the levels of nitric oxide (NO), interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) elevated by LPS. Similarly, cordycepin decreased the secretion of NO, TNF-α, and IL-6. Additionally, LPS-induced expression of toll-like receptor 4 (TLR4) and inflammatory proteins (iNOS, COX-2, TNF-α, and IL-6) was significantly suppressed by cordycepin. Molecular docking revealed that cordycepin binds to the TLR4/MD2 complex (−6.2 kcal/mol) at Lys341, Ser364, and Phe365, suggesting competitive inhibition at the LPS-binding site. These findings indicate that cordycepin attenuates LPS-induced neuroinflammation by modulating the TLR4 signaling pathway, highlighting its therapeutic potential for neuroinflammatory conditions.