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OBJECTIVE Compound FLZ is a novel synthetic squamosamide cyclic analogue with several phenolichydroxy groups.Previous researches have demonstrated that FLZ exhibits strong anti-oxidative and neuroprotective activities in AD and PD models.Hyperhomocysteinemia (HHcy) is believed to induce endothelial dysfunction, which is an independent risk factor for atherosclerosis and vascular diseases.This study was designed to examine whether FLZ has protective effect against HHcy-induced primary cultured rat brain microvascular endothelial cells (rBMEC) injury.METHODS Cell survival was measured by MTT assay.Cell nuclei were observed by Hochest 33342 staining.Senescent cells were detected by senescence associated β-galactosidase (SA-β-gal) staining.ROS was measured by DCF fluorescent microscopy.The NO production and NOS activity were measured by biochemical methods.HHcy-induced expression of NF-κB, p53, Noxa and Fas, the release of mitochondrial cytochrome c were measured by Western blot analysis.RESULTS In this study, we found that FLZ (0.1-10 μmol· L-1) may antagonize homocysteine (1 mmol· L-1) induced cell death (88% when FLZ was 10 μmol·L-1 vs.55% for Hcy, P <0.001) and apoptosis, senescent cells increase, which were correlated with the decrease of ROS accumulation, NO production and NOS activity.Western blotting analyses showed FLZ could inhibit the activation of NF-κB, upregulation of p53, Noxa and Fas.Pretreatment of FLZ also blocked mitochondrial cytochrome c release.CONCLUSION These findings suggest that FLZ has protective action against HHcy-induced toxicity in rBMECs, which may have implications FLZ may have therapeutic potential for the prevention of cardiovascular diseases.