17 beta-estradiol protects SH-SY5Y cells against HIV-1 gp120-induced cell death: Evidence for a role of estrogen receptors

Despite the large body of experimental evidence demonstrating the neuroprotective properties of 17β-estradiol (17β-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 17β-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 17β-E2 protects human SH-SY5Y neuroblastoma cells from cell death elicited by gp120. Tamoxifen and ICI 182,780, two ER antagonists, both antagonized 17β-E2-mediated inhibition of cell death. Exposure of SH-SY5Y cells to gp120 for 30 min caused a significant accumulation of intracellular reactive oxygen species (ROS) and this was abrogated by 17β-E2; however, the ability of 17β-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 17β-E2 though it was able to revert prevention of cell death. Furthermore, by using 17α-E2, the isomer unable to stimulate ER which, however, retains the antioxidant effects, we observed that a pre-treatment with 17α-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 17β-E2 is receptor-mediated and ROS scavenging effects may not be implicated