Estrogen Action in Neuroprotection and Brain Inflammation

The fertile period of women's life compared to menopause is associated with a lower incidence of degenerative inflammatory diseases. In brain, estrogens ameliorate brain performance and have positive ef- fects on selected neural pathologies characterized by a strong inflamma- tory component. We thus hypothesized that the inflammatory response is a target of estrogen action; several studies including ours provided strong evidence to support this prediction. Microglia, the brain's inflammatory cells, and circulating monocytes express the estrogen receptors ER-� and ER-� and their responsiveness in vivo and in vitro to pro-inflammatory agents, such as lipopolysaccharide (LPS), is controlled by 17� -estradiol (E2). Susceptibility of central nervous system (CNS) macrophage cells to E2 is also preserved in animal models of neuroinflammatory diseases, in which ER-� seems to be specifically involved. At the molecular level, induction of inflammatory gene expression is blocked by E2. We recently observed that, differently from conventional anti-inflammatory drugs, E2 stimulates a nongenomic event that interferes with the LPS signal transduction from the plasma membrane to cytoskeleton and intracellu- lar effectors, which results in the inhibition of the nuclear translocation of NF-� B, a transcription factor of inflammatory genes. Interference with NF-� B intracellular trafficking is selectively mediated by ER-� .I n summary, evidence from basic research strongly indicates that the use of estrogenic drugs that can mimic the anti-inflammatory activity of E2 might trigger beneficial effects against neurodegeneration in addition to carrying out their specific therapeutic function.