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a Center of Excellence on Neurodegenerative Diseases, Department of Pharmacological Sciences, University of Milan, Via Balzaretti, 9, 20133 Milan, Italy
Key Words: estrogen receptors • inflammation • neurodegeneration
Address for correspondence: Elisabetta Vegeto, Ph.D., Center of Excellence on Neurodegenerative Diseases, Department of Pharmacological Sciences, University of Milan, Via Balzaretti, 9, 20133 Milan, Italy. Voice: 0039-0250318263; fax: 0039-0250318284. e-mail: elisabetta.vegeto{at}unimi.it
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 effects on selected neural pathologies characterized by a strong inflammatory 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 intracellular 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-. In 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.
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