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Aim: To investigate the anti-inflammatory and neuroprotective effects of (5R)-5-hydroxytriptolide (LLDT-8) following cerebral ischemia/reperfusion injury.Methods: ICR mice were subjected to transient middle cerebral artery occlusion (tMCAO) and LLDT-8 (0.5mg/kg and 1mg/kg) was administrated at the onset of occlusion.Infarct volumes were estimated with 2,3,5-triphenyltetrazolium chloride (TTC) staining at 24 h after MCAO.Real-Time PCR was performed to detect mRNA levels of TNF-α, IL-1β, iNOS in cortical penumbra.In vitro studies, the mRNA expression of the above-mentioned pro-inflammatory cytokines was also determined in LPS-stimulated mouse microglial BV-2 cells and primary microglia.The concentrations of TNF-α and IL-1O in culture media were assessed by ELISA.The production of nitric oxide (NO) in the supernatants was measured by Griess reagent.Nuclear translocation of NF-κB was evaluated by immunofluorescence.phosphorylation of Iκ Bαwas analyzed with Western blot.The neuroprotective effect of LLDT-8 was determined with the in vitro glia/neuron co-culture system.Results: LLDT-8 significantly reduced infarct sizes and mRNA expression of pro-inflammatory cytokines in the cortex compared to the saline group.LLDT-8 inhibited NO release and mRNA expression of TNF-α, IL-1βand iNOS in BV-2 and primary microglia treated with LPS(P<0.05).In addition, LLDT-8 suppressed degradation of Iκ Bαand inhibited the nuclear translocation of NF-κB.Moreover, LLDT-8 protected neuron cells from the inflammation-induced injury in the microglia/neuronal co-culture system.Conclusion: LLDT-8 exerted anti-inflammatory and protected against acute cerebral ischemia/reperfusion injury.It inhibited LPS-induced microglial activation by blocking the Iκ B/NF-κB signaling pathway.