Anti-apoptotic effect of SERM on the amyloid-β-induced apoptosis in PC12

雌激素（E2）对神经元具有直接的体内和体外作用，如诱导神经突生长。我们研究了E2诱导神经母细胞瘤（SH-SY5Y）细胞的形态学变化和胞内信号通路。用SH-SY5Y细胞检测醋酸甲羟孕酮（MPA）或孕酮（P4）对e2诱导的神经突生长的影响。E2通过磷酸化Akt和细胞外信号调节激酶（ERK）诱导神经突生长。除ERK磷酸化外，E2的这些作用均被MPA而非P4所消除。黄体酮受体拮抗剂RU486阻断了MPA的抑制作用。雌激素受体拮抗剂ICI 182、780和磷脂酰肌醇3-激酶抑制剂LY294002抑制e2诱导的神经突生长。由于Rho家族的小gtpase已被证明参与神经突生长的调节，我们研究了Rac1， Cdc42和RhoA在e2诱导的神经突生长中的串扰。E2立即增加了Rac1和Cdc42活性，降低了RhoA活性。在表达Rac1或Cdc42显性阴性突变体的细胞中，e2诱导的神经突生长减弱。这些结果表明，E2对Rho家族GTPase活性的调节对神经母细胞瘤细胞的神经突生长很重要，并且MPA可能对E2有拮抗作用，而P4则没有。

Estrogen (E2) has direct in vivo and in vitro effects, such as inducing neurite outgrowth, on neurons. We investigated the morphological changes and intracellular signaling pathway induced by E2 in neuroblastoma (SH-SY5Y) cells. The effect of medroxyprogesterone acetate (MPA) or progesterone (P4) on the E2-induced neurite outgrowth was also examined using SH-SY5Y cells. Neurite outgrowth was induced by E2 in association with the phosphorylation of both Akt and extracellular signal-regulated kinase (ERK). These effects of E2, except for ERK phosphorylation, were abolished by MPA but not by P4. Progesterone receptor antagonist RU486 blocked the inhibitory effects of MPA. Estrogen receptor antagonist ICI 182, 780 and phosphatidylinositol 3-kinase inhibitor LY294002 inhibited the E2-induced neurite outgrowth. Because the Rho family of small GTPases has been shown to be involved in the regulation of neurite outgrowth, we examined the cross-talk among Rac1, Cdc42 and RhoA in the E2-induced neurite outgrowth. E2 immediately increased the Rac1 and Cdc42 activity and decreased the RhoA activity. E2-induced neurite outgrowth was attenuated in cells expressing dominant-negative mutants for Rac1 or Cdc42. These results suggest that regulation of Rho family GTPase activity by E2 is important for the neurite outgrowth in neuroblastoma cells, and that MPA, but not P4, may have an antagonistic effect against E2.