Estrogen attenuates gp120-and tat(1-72)-induced oxidative stress and prevents loss of dopamine transporter function

Postmenopausal women who are infected with HIV are at risk for experiencing dementia and Parkinson's-like symptoms associated with low levels of estrogen. Neurotoxic damage leading to these symptoms may involve HIV-associated proteins gp120 and/or tat(1-72) (tat). Our hypothesis is that 17 beta-Estradiol (E-2) is an effective agent for protection against gp120/tat-induced damage associated with increased oxidative stress, with particular focus on peroxynitrite-induced oxidative stress. We used SK-N-SH cells and striatal synaptosomes from Sprague-Dawley rats as model systems to assess neuroprotection by E-2. Cells coincubated with SIN-1 (3-morpholinosydnonimine) or tat and gp120, together or separately, significantly increased oxidative stress on the SK-N-SH cells, as indicated by the increase in the levels of dichlorofluorescein (DCFH) fluorescence. These data suggest that a component of tat and gp120 neurotoxicity may be due to increased oxidative stress. Coincubation with E-2 attenuated tat- and gp120-induced increase in fluorescence. Coincubation with progesterone had no effect on tat-induced fluorescence, whereas coincubation with the E-2 antagonist ICI 182,780 and E-2 completely prevented the effects observed with E-2 alone. Both gp120 and tat decreased [H-3] dopamine uptake into striatal synaptosomes by decreasing the V-max of the dopamine transporter (DAT). Pretreatment of synaptosomes with E-2 (100 nM) partially reversed this reduction. In conclusion, E-2 appears to be effective for preventing the oxidative stress and loss of DAT function associated with gp120/tat neurotoxicity.