Estrogen Action in Neuroprotection and Brain Inflammation

Abstract

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-alpha and ER-beta and their responsiveness in vivo and in vitro to pro-inflammatory agents, such as lipopolysaccharide (LPS), is controlled by 17beta-estradiol (E(2)). Susceptibility of central nervous system (CNS) macrophage cells to E(2) is also preserved in animal models of neuroinflammatory diseases, in which ER-alpha seems to be specifically involved. At the molecular level, induction of inflammatory gene expression is blocked by E(2). We recently observed that, differently from conventional anti-inflammatory drugs, E(2) 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-kappaB, a transcription factor of inflammatory genes. Interference with NF-kappaB intracellular trafficking is selectively mediated by ER-alpha. In summary, evidence from basic research strongly indicates that the use of estrogenic drugs that can mimic the anti-inflammatory activity of E(2) might trigger beneficial effects against neurodegeneration in addition to carrying out their specific therapeutic function.

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…However, other cellular targets may underscore estrogen neuroprotective activity in the CNS: (i) neurons, through hormone anti-apoptotic and neurotrophic actions; (ii) neural stem cells, by inducing their proliferation; (iii) astroglial cells, by increasing their potential for secreting neuroprotective molecules or decreasing the production of neurotoxic agents; (iv) endothelial cells, on which estrogens act to reduce adhesion molecule expression and other factors that recruit circulating leukocytes ( [144,187]). …”

Aging and substitutive hormonal therapy influence in regional and subcellular distribution of ERα in female rat brain

“…Estrogens are also able to prevent neuronal death in several models of brain injury (Liu et al 2010), to ameliorate brain inflammation (Pozzi et al 2006), and to be implicated in many neurological disorders as Parkinson's disease (Baraka et al 2011) and Alzheimer's disease promoting the nonamyloidogenic metabolism of the amyloid precursor protein (Jaffe et al 1994).…”

Gender and the Pathogenesis of Gastrointestinal Diseases: The Role of Steroid Sex Hormones in the Development

“…Vascularsmooth muscle and endothelial cells have been reported to express ERα and Erβ protein & mRNA [34][35][36]. Oestrogen has been proved to have anti-inflammatory effect by acting against inflammatory promoters, such as bacterial cell wall component, lipopolysaccharide (LPS) via activating ERα [37][38][39][40][41][42].…”