Mechanisms of estrogenic protection against gp120-induced neurotoxicity.
gp120, an HIV coat glycoprotein that may play a role in AIDS-related dementia complex (ADC), induces neuronal toxicity characterized by NMDA receptor activation, accumulation of intracellular calcium, and downstream degenerative events including generation of reactive oxygen species and lipid peroxidation. We have previously demonstrated estrogenic protection against gp120 neurotoxicity in primary hippocampal cultures. We here characterize the mechanism of protection by blocking the classical cytosolic estrogen receptors and by measuring oxidative end points including accumulation of extracellular superoxide and lipid peroxidation. Despite blocking ERalpha and ERbeta with 1 microM tamoxifen, we do not see a decrease in the protection afforded by 100 nM 17 beta-estradiol against 200 pM gp120. Additionally, 17alpha-estradiol, which does not activate estrogen receptors, protects to the same extent as 17beta-estradiol. 17beta-Estradiol does, however, decrease gp120-induced lipid peroxidation and accumulation of superoxide. Together the data suggest an antioxidant mechanism of estrogen protection that is independent of receptor binding.
Howard
S A
SA
Department of Biological Sciences, Stanford University, Stanford, California 94305, USA.
Brooke
S M
SM
Sapolsky
R M
RM
D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D006624:Hippocampus; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology; D013481:Superoxides / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology
D004965:Estrogen Antagonists; D015699:HIV Envelope Protein gp120; D011960:Receptors, Estrogen; D013629:Tamoxifen; D013481:Superoxides; D004958:Estradiol