Experimental evidence supports a neuroprotective and neurotrophic role for the gonadal steroid hormone estrogen in the mammalian central nervous system (CNS) both under normal and pathological conditions though the underlying mechanisms are not yet fully understood (Garcia-Segura et al., 2001; Mooradian, 1993). During the last decade we have used human neuroblastoma cell cultures to study in vitro the mechanisms of neuronal death caused by human immunodeficiency virus type 1 (HIV-1) coat protein, gp120, known to be the major aetiologic agent of the neuronal loss reported post-mortem in the brain cortex of AIDS patients (Corasaniti et al., 2001). Using this in vitro experimental model here we now report that 17β- estradiol (E2) provides neuroprotection against gp120 toxicity and this seems to occur via estradiol receptor-mediated mechanism.

SH-SY5Y neuroblastoma cells (passages 20-24) were exposed to gp120 (10 pM) given alone or in the presence of E2 or 17-E2, the isomer unable to stimulate the receptor-mediated pathway which, however, retains the antioxidant effects (see Garcia-Segura et al., 2001). Under these experimental conditions, a pretreatment with E2 (0.1 and 1.0 µM; n=3 independent experiments per concentration with n=8 per each experiment) or with 17-E2 (0.1 and 1.0 µM; n=3 experiments per concentration with n=8 for each experiment) is effective in preventing (P>0.05 vs control one way ANOVA with post-hoc Tukey-Kramer multiple comparison) accumulation of intracellular reactive oxygen species (ROS) induced by gp120 (P<0.05 vs control) and estimated by 2’,7’-dichlorodihydrofluorescein diacetate (Mattson et al., 1995). At variance with E2, 17-E2 (0.1 µM, n=6 experiments) was unable (P>0.05 vs gp120) to counteract cell death caused bythe viral protein (n=6 experiments; P<0.01 vs control) and evaluated by trypan blue staining. Preincubation of SH-SY5Y neuroblastoma cells with two E2 receptor antagonists, e.g. ICI-182-780 (1 µM) and tamoxifen (0.1 µM) reverted the neuroprotective effects induced by E2 (0.1 µM; n= 6; P<0.01 vs gp120) against gp120-caused cell death (n=6 experiments per group; P<0.01 vs control); at lower concentrations ICI-182-780 (0.1 µM; n=6 eXperiments) and tamoxifen (0.01 µM, n= 6 experiments) were ineffective (P<0.01 vs gp120). By contrast, under these experimental conditions, ICI-182-780 (1 µM; n=5 independent experiments with n=8 per each experiment) failed (P>0.05 vs gp120+E2) to revert intracellular ROS reduction caused by E2 in gp120-treated cells.

Collectively, these data demonstrate that neuroprotection afforded by E2 is receptor-mediated and ROS scavenging effect may not be implicated.

Corasaniti et al . (2001) J. Neurochem . 79, 1-8.
Garcia-Segura et al . (2001) Prog. Neurobiol . 63, 29-60.
Mattson et al . (1995) Meth. Cell Biol . 46, 187-216.
Mooradian A.D. (1993) J. Steroid Biochem. Mol. Biol ., 45, 509-511.

Financial support from the IV AIDS Programme (ISS, Rome) is gratefully acknowledged.