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 Ab25-35 -induced toxicity. The potential mechanisms were studied by Western blotting in cultured rat pheochromocytoma cells (PC12 cells). Results RLX(1 000 nmol/L), in combination with Ab25-35 (30 mmol/L), increased the cell viability (P<0.001), and reduced the number of apoptotic cells (P<0.05). RLX attenuated Ab25-35-induced loss of Dym (P<0.01). The changing of Dym 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). Ab25-35 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 Ab25-35 and RLX, Ab25-35-induced phosphorylation of p38MAPK and JNK were inhibited (P<0.01 and P<0.001, respectively). Conclusion RLX inhibited Ab25-35-induced cell apoptosis by activating the ERK1/2 pathway in PC12 cells. RLX also attenuated Ab25-35-induced activation of p38MAPK and JNK. The mitochondria pathway was involved in this inhibitory effect. 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 Ab25- 35 -induced toxicity. The potential mechanisms were studied by Western blotting in cultured rat pheochromocytoma cells (PC12 cells). Results RLX (1000 nmol / L), in combination with Ab25-35 (30 mmol / L) (P <0.001), and reduced the number of apoptotic cells (P <0.05). RLX attenuated Ab25-35-induced loss of Dym (P <0.01). The changing of Dym 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 (i In PC12 cells treated solely with RLX, ERK1 / 2 was activated (P <0.01). In PC12 cells treated with Ab25-35 and RLX, Ab25 -35-induced phosphorylation of p38MAPK and JNK were inhibited (P <0.01 and P <0.001, respectively). Conclusion RLX inhibited Ab25-35-induced cell apoptosis by activating the ERK1 / 2 pathway in PC12 cells. RLX also attenuated Ab25-35 -induced activation of p38MAPK and JNK. The mitochondria pathway was involved in this inhibitory effect.