a b s t r a c tRecent studies highlight the prominent role played by estrogens in protecting the central nervous system (CNS) against the noxious consequences of a chronic inflammatory reaction. The neurodegenerative process of several CNS diseases, including Multiple Sclerosis, Alzheimer's and Parkinson's Diseases, is associated with the activation of microglia cells, which drive the resident inflammatory response. Chronically stimulated during neurodegeneration, microglia cells are thought to provide detrimental effects on surrounding neurons. The inhibitory activity of estrogens on neuroinflammation and specifically on microglia might thus be considered as a beneficial therapeutic opportunity for delaying the onset or progression of neurodegenerative diseases; in addition, understanding the peculiar activity of this female hormone on inflammatory signalling pathways will possibly lead to the development of selected anti-inflammatory molecules. This review summarises the evidence for the involvement of microglia in neuroinflammation and the anti-inflammatory activity played by estrogens specifically in microglia.

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.

In female animals, energy metabolism and fertility are tightly connected, and reciprocally regulated. However, the relative contributions of metabolic and reproductive pathways have changed over the course of evolution. In oviparous animals, metabolic factors take precedence over fertility, enabling egg production to be inhibited in a nutritionally poor environment. By contrast, in placental mammals, the opposite occurs: the need to feed a developing embryo and neonate forces metabolic pathways to adapt to these reproductive needs. This physiological necessity explains why in female mammals alterations of gonadal activity, including age-dependent cessation of ovarian functions, are associated with a disruption of metabolic homeostasis and consequent inflammatory reactions that trigger the onset of metabolic, cardiovascular, skeletal and neural pathologies. This Review discusses how metabolic homeostasis and reproductive functions interact to optimize female fertility and explains the pathogenic mechanisms underlying the disordered energy metabolism associated with human ovarian dysfunction owing to menopause, polycystic ovary syndrome and Turner syndrome. Finally, this article highlights how hormone replacement therapy might aid the restoration of metabolic homeostasis in women with ovarian dysfunction.

Although several lines of evidence have indicated that menopause is associated with increased susceptibility to neurological disorders, the mechanisms involved in this phenomenon remain to be elucidated. Because neuroinflammation is a common feature of a number of brain diseases, we hypothesized that the cessation of ovarian functions and the consequent decrease in estrogen receptor (ER)-mediated antiinflammatory activity may represent a trigger for postmenopausal brain dysfunctions. The aim of the present study was to investigate the effects of aging and surgical menopause on the activity of ER in neuroinflammation. The present study shows that ER genes are expressed in the hippocampus, but ER transcriptional activity decreases significantly beginning at 12 months of age in intact and ovariectomized mice. With ovariectomy, we observe an age-dependent accumulation of mRNA encoding inflammatory mediators (e.g. TNFα, IL1β, and macrophage inflammatory protein-2) and changes in the morphology of astroglia and microglia. In addition, we show that aging itself is coupled with an exaggerated response to acute inflammatory stimuli with a major accumulation of TNFα, IL1β, macrophage inflammatory protein-2, and macrophage chemoattractant protein-1 mRNA in response to lipopolysaccharide administration. The response to acute inflammatory stimuli appears to be differentially modulated by the duration of hormone deprivation in 12-month-old mice. Taken together, the present results show that aging is associated with decreased ER activity, despite continuous ER synthesis, and that age-dependent neuroinflammation is strongly influenced by hormone deprivation.

Background: The mechanism of motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is poorly understood.Results: The peroxisome proliferator-activated receptor γ (PPARγ) can be activated by lipid peroxidation metabolites in ALS motor neurons, and this can prompt the expression of antioxidant enzymes.Conclusion: PPARγ can exert a direct protective effect in ALS motor neurons.Significance: PPARγ transcriptional co-activators may represent therapeutic targets in ALS.