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Published on: August 15, 2012
Estrogenic protection against gp120 neurotoxicity: role of microglia
Ilona Zemlyak1, Sheila Brooke, Robert Sapolsky
1Department of Biological Sciences, Neurology and Neurological Sciences, Stanford University, CA 94305-5020, USA. ilona.zemlyak@stanford.edu
Abstract:
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.
Insights
Estrogen reduces neurotoxicity caused by HIV's gp120 protein. It primarily works by decreasing harmful factors released by microglia, with a smaller effect on enhancing neuron survival.
Area of Science:
- Neuroscience
- Immunology
- Endocrinology
Background:
- HIV infection can lead to nervous system damage (neurotoxicity).
- The HIV glycoprotein gp120 is implicated in this neurotoxicity.
- Estrogen has shown potential in mitigating gp120-induced neurotoxicity.
Purpose of the Study:
- To investigate if estrogen reduces the toxicity of factors released by gp120-stimulated microglia.
- To determine if estrogen enhances neuronal resilience against these toxic factors.
Main Methods:
- Established separate microglial, mixed neuronal/glial hippocampal, and neuron-enriched cultures.
- Manipulated gp120 and estrogen exposure in these cultures.
- Assessed neurotoxicity using conditioned media from gp120-treated microglia.
Main Results:
- Estrogen demonstrated a minor protective effect by increasing neuronal resistance.
- The primary protective action of estrogen was found to be reducing the neurotoxicity of microglial-released factors.
Conclusions:
- Estrogen's neuroprotective effects against HIV gp120 involve both bolstering neuronal defense and, more significantly, reducing microglial-derived neurotoxins.
