Russo Rossella, Navarra Michele, Maiuolo Jessica, Rotiroti Domenicantonio, Bagetta Giacinto, Corasaniti Maria Tiziana
Department of Pharmacobiological Sciences, Faculty of Pharmacy, University Magna Graecia of Catanzaro, c/o Complesso Ninì Barbieri, 88021 Roccelletta di Borgia, Catanzaro, Italy.
Neurotoxicology. 2005 Oct;26(5):905-13. doi: 10.1016/j.neuro.2005.01.009.
Despite the large body of experimental evidence demonstrating the neuroprotective properties of 17beta-estradiol (17beta-E2) both in vitro and in vivo experimental models of neuronal injury, the exact mechanisms implicated in neuroprotection have not been fully delineated. Some experimental evidence highlight a role for the antioxidant properties of 17beta-E2 in mediating protection against oxidative injury. Parallel to these, evidence also exist which point to alternative mechanisms involving estrogen receptors (ER). The HIV-1 coat protein, gp120, has been implicated in the progression of central nervous system damage caused by HIV-1 infection. The neurotoxic effects induced by gp120 are triggered via an excitotoxic mechanism of cell death which implicates alteration of calcium homeostasis, activation of calcium-dependent pathways, mitochondrial uncoupling and membrane lipid peroxidation. In the present study, we demonstrate that 17beta-E2 protects human SH-SY5Y neuroblastoma cells from cell death elicited by gp120. Tamoxifen and ICI 182,780, two ER antagonists, both antagonized 17beta-E2-mediated inhibition of cell death. Exposure of SH-SY5Y cells to gp120 for 30min caused a significant accumulation of intracellular reactive oxygen species (ROS) and this was abrogated by 17beta-E2; however, the ability of 17beta-E2 to counteract ROS generation induced by gp120 does not account for the reported prevention of cell death because ICI 182,780 failed to revert intracellular ROS reduction caused by 17beta-E2 though it was able to revert prevention of cell death. Furthermore, by using 17alpha-E2, the isomer unable to stimulate ER which, however, retains the antioxidant effects, we observed that a pre-treatment with 17alpha-E2 was effective in preventing gp120-induced accumulation of ROS but it failed to affect cell death caused by the viral protein. Collectively, these data demonstrate that neuroprotection afforded by 17beta-E2 is receptor-mediated and ROS scavenging effects may not be implicated.
尽管大量实验证据表明17β-雌二醇（17β-E2）在体外和体内神经元损伤实验模型中均具有神经保护特性，但神经保护的确切机制尚未完全阐明。一些实验证据突出了17β-E2的抗氧化特性在介导抗氧化损伤保护中的作用。与此平行的是，也有证据指向涉及雌激素受体（ER）的其他机制。HIV-1包膜蛋白gp120与HIV-1感染所致中枢神经系统损伤的进展有关。gp120诱导的神经毒性作用是通过细胞死亡的兴奋性毒性机制触发的，这涉及钙稳态的改变、钙依赖性途径的激活、线粒体解偶联和膜脂质过氧化。在本研究中，我们证明17β-E2可保护人SH-SY5Y神经母细胞瘤细胞免受gp120诱导的细胞死亡。他莫昔芬和ICI 182,780这两种ER拮抗剂均拮抗17β-E2介导的细胞死亡抑制作用。将SH-SY5Y细胞暴露于gp120 30分钟会导致细胞内活性氧（ROS）显著积累，而17β-E2可消除这种积累；然而，17β-E2抵消gp120诱导的ROS生成的能力并不能解释所报道的对细胞死亡的预防作用，因为ICI 182,780虽然能够逆转细胞死亡的预防作用，但未能恢复由17β-E2引起的细胞内ROS减少。此外，通过使用17α-E2，这种异构体不能刺激ER，但保留了抗氧化作用，我们观察到用17α-E2预处理可有效预防gp120诱导的ROS积累，但未能影响病毒蛋白引起的细胞死亡。总体而言，这些数据表明17β-E2提供的神经保护是受体介导的，可能与ROS清除作用无关。
