Estrogen attenuates gp120- and tat1-72-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 17beta-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 [(3)H] 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.
Wallace
David R
DR
Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, Tulsa, 74107, USA. walladr@chs.okstate.edu
Dodson
Stephanie
S
Nath
Avindra
A
Booze
Rosemarie M
RM
D000818:Animals; D045744:Cell Line, Tumor; D003342:Corpus Striatum / Q000166:cytology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D005452:Fluoresceins / Q000378:metabolism; D015696:Gene Products, tat / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009447:Neuroblastoma; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014316:Tritium / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D005452:Fluoresceins; D015696:Gene Products, tat; D015699:HIV Envelope Protein gp120; D054322:tat Gene Products, Human Immunodeficiency Virus; C470431:tat peptide (1-72), Human immunodeficiency virus 1; D014316:Tritium; C029569:diacetyldichlorofluorescein; D004958:Estradiol; C002385:linsidomine; D008981:Molsidomine; D004298:Dopamine