Estrogenic protection against gp120 neurotoxicity: role of microglia.
HIV infection of the nervous system can cause neurotoxicity, and the glycoprotein gp120 of HIV seems to play a key role in this. gp120 is neurotoxic through a multi-cellular pathway, stimulating microglia to release excitotoxins, cytokines and reactive oxygen species, which then damage neurons. We have previously shown that estrogen decreases the neurotoxicity of gp120 in mixed neuronal/glial cultures. In this study, we determine whether estrogen a) decreases the collective neurotoxicity of the factors released by gp120-treated microglia, and/or b) enhances the ability of neurons to survive such factors. To do so, we established microglial cultures, mixed neuronal/glial hippocampal cultures, and neuron-enriched cultures, independently manipulating gp120 and estrogen exposure in each type of culture, and inducing neurotoxicity in neuron-containing cultures by introducing conditioned media from gp120-treated microglial cultures. We observe that estrogen can exert some small protective effects at the level of bolstering neuronal resistance, but that the bulk of its protective effects arise at the level of decreasing the neurotoxicity of factors released by microglia.
Zemlyak
Ilona
I
Department of Biological Sciences, Neurology and Neurological Sciences, Stanford University, CA 94305-5020, USA. ilona.zemlyak@stanford.edu
Brooke
Sheila
S
Sapolsky
Robert
R
D000704:Analysis of Variance; D000818:Animals; D001685:Biological Factors / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D001685:Biological Factors; D017077:Culture Media, Conditioned; D015699:HIV Envelope Protein gp120; D018696:Neuroprotective Agents; D009498:Neurotoxins; D004958:Estradiol