SILVIA POZZI^a, VALERIA BENEDUSI^a, ADRIANA MAGGI^a AND ELISABETTA VEGETO^a

^a Center of Excellence on Neurodegenerative Diseases, Department of Download to dtalton manager Pharmacological Sciences, University of Milan, Via Balzaretti, 9, 20133 Milan, Italy.

Elisabetta Vegeto, Ph.D., Center of G°°gle ScholarExcellence on Neurodegenerative Diseases, Department of Articles by POZZI, S. Pharmacological Sciences, University of Milan, Via Balzaretti, 9, 20133 Articles by VEGETO E Milan, Italy. Voice:0039-0250318263; fax: 0039-0250318284; E-mail: [email protected].

Key Words: estrogen receptors • inflammation • neurodegeneration.

The fertile period of women's life compared to menopause is PubMed associated with a lower incidence of degenerative inflammatory PubMed Citation diseases. In brain, estrogens ameliorate brain performance and Articles by POZZI S 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- α and ER-β and their responsiveness in vivo and in vitro to pro-inflammatory agents, such as lipopolysaccharide (LPS), is controlled by 17β-estradiol (E₂). Susceptibility of central nervous system (CNS) macrophage cells to E₂ is also preserved in animal models of neuroinflammatory diseases, in which ER-α 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 antiinflammatory 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-kB, a transcription factor of inflammatory genes. Interference with NF-kB intracellular trafficking is selectively mediated by ER-α. 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.