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A large body of evidence has suggested a strong association between neuroinflammation and the pathogenesis of many neurodegenerative diseases. Therefore, it is a good target for therapeutic treatment. So far, studies have proven anti-inflammatory herbal medicine and its constituents to be effective in slowing down the neurodegenerative process. The present study tested tripchlorolide, an extract of Tripterygium wilfordii Hook F (TWHF), as a novel agent to suppress inflammatory process in microglia. It showed this novel agent to be cytotoxic at a dose of 20−40 nM to primary microglia and BV-2 microglial cells but not to primary cortical neurons and Neuro-2A cells in vitro. Moreover, tripchlorolide protected primary cortical neurons and Neuro-2A cells from neuroinflammatory toxicity induced by the conditioned media from lipopolysaccharide (LPS)-stimulated microglia, which resulted in a significant decrease in their cell survival. The changes of the inflammatory mediators in this process were further investigated. In the LPS-stimulated microglia, the production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), nitric oxide (NO), prostaglandin E2 (PGE2), and intracellular superoxide anion (SOA) was markedly attenuated by tripchlorolide at a dose of 1.25−10 nM in a dose-dependent manner. Furthermore, the production of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was also significantly inhibited by tripchlorolide in both mRNA and protein levels. These results suggest that tripchlorolide can protect neuronal cells via a mechanism involving inhibition of inflammatory responses of microglia to pathological stimulations. Therefore, it is potentially a highly effective therapeutic agent in treating neuroninflammatory diseases.