Objective To investigate the neuroprotective effects and the mechanism of this protection of raloxifene (RLX),a selective estrogen receptor modulator.Methods MTT assay and flow cytometry with annexin V-FITC/PI staining were performed to evaluate the neuroprotective effects of RLX on Aβ25-35-induced toxicity.The potential mechanisms were studied by West blotting in cultured rat pheochromocytoma cells (PC12 cells).Results RLX(1 000 nmol/L),in combination with Aβ25-35 (30 tmol/L),increased the cell viability (P ＜0.001),and reduced the number of apoptotic cells (P ＜0.05).RLX attenuated Aβ25-35-induced loss of △ψm ( P ＜0.01).The changing of △ψm was similar to the variation of apoptosis.PD98059 (inhibitor of ERK1/2) inhibited the effects of RLX on cell viability and phosphorylation of cleaved caspase-9.No significant difference of cell viability or phosphorylation of cleaved caspase-9 had been found when PC12 cells were incubated with SB203580 (inhibitor of p38MAPK) or SP600125 (inhibitor of JNK).Aβ25-35 induced a time-dependent phosphorylation of p38MAPK and JNK.In PC12 cells treated solely with RLX,ERK1/2 was activated (P＜0.01).In PC12 cells treated with Aβ25-35 and RLX,Aβ25-35-induced phosphorylation of p38MAPK and JNK were inhibited (P＜0.01 and P＜0.001,respectively).Conclusion RLX inhibited Aβ25-35-induced cell apoptosis by activating the ERK1/2pathway in PC12 cells.RLX also attenuated Aβ25-35-induced activation of p38MAPK and JNK.The mitochondria pathway was involved in this inhibitory effect.