title: 17beta-estradiol protects SH-SY5Y Cells against HIV-1 gp120-induced cell death: evidence for a role of estrogen receptors.
abstract: 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.
authors.affiliation: Department of Pharmacobiological Sciences, Faculty of Pharmacy, University Magna Graecia of Catanzaro, c/o Complesso Ninì Barbieri, 88021 Roccelletta di Borgia, Catanzaro, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Russo
authors.forename: Michele
authors.initials: M
authors.lastname: Navarra
authors.forename: Jessica
authors.initials: J
authors.lastname: Maiuolo
authors.forename: Domenicantonio
authors.initials: D
authors.lastname: Rotiroti
authors.forename: Giacinto
authors.initials: G
authors.lastname: Bagetta
authors.forename: Maria Tiziana
authors.initials: MT
authors.lastname: Corasaniti
mesh_terms: D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D000077267:Fulvestrant; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D004965:Estrogen Antagonists; D015699:HIV Envelope Protein gp120; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol