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Expression of proinflammatory molecules by glial cells is involved in the pathophysiological changes associated with chronic neurological diseases. Under pathological conditions, astrocytes release a number of proinflammatory molecules, such as interleukin-6 (IL-6) and interferon-gamma-inducible protein-10 (IP-10). The ovarian hormone estradiol exerts protective effects in the central nervous system that, at least in part, may be mediated by a reduction of local inflammation. This study was designed to assess whether estradiol affects the production of IL-6 and IP-10 by primary cultures of newborn mice astrocytes exposed to lipopolysaccharide (LPS), a bacterial endotoxin known to cause neuroinflammation. In addition, the possible anti-inflammatory effect of several selective estrogen receptor modulators (SERMs) was also assessed. LPS induced an increase in the expression of IL-6 and IP-10 mRNA levels in astrocytes and an increase in IL-6 and IP-10 protein levels in the culture medium. These effects of LPS were impaired by estradiol and by the four SERMs tested in our study: tamoxifen, raloxifene, ospemifene, and bazedoxifene. All SERMs tested showed a similar effect on IL-6 and IP-10 mRNA levels, but raloxifene and ospemifene were more effective than tamoxifen and bazedoxifene in reducing protein levels in LPS-treated cultures. Finally, we report that news SERMs, ospemifene and bazedoxifene, exert anti-inflammatory actions by a mechanism involving classical estrogen receptors and by the inhibition of LPS-induced NFkappaB p65 transactivation. The results suggest that estrogenic compounds may be candidates to counteract brain inflammation under neurodegenerative conditions by targeting the production and release of proinflammatory molecules by astrocytes.

Although discovered in 2000, neuroglobin (Ngb) functions are still uncertain. A contribution to the role played by Ngb in neurons could certainly derive from the identification of Ngb endogenous modulators. Here, we evaluate the possibility that Ngb could be regulated by 17β-estradiol (E₂) signaling in both SK-N-BE human neuroblastoma cell line and mouse hippocampal neurons. 1 nM E₂ rapidly induced a 300% increase in Ngb levels in both models. The E₂ effect was specific, being not induced by testosterone or dihydrotestosterone. The E₂-induced Ngb increase requires estrogen receptor (ER) β, but not ERα, as evaluated by the mimetic effect of ERβ-specific agonist DPN and by the blockage of E₂ effect in ERβ-silenced SK-N-BE cells. Furthermore, both rapid (15 min) ERβ-dependent activation of p38/MAPK and transcriptional ERβ activity were required for the estrogenic regulation of Ngb. Finally, E₂ exerted a protective effect against H₂O₂-induced neuroblastoma cell death which was completely prevented in Ngb-silenced cells. Overall, these data suggest that Ngb is part of the E₂ signaling mechanism that is activated to exert protective effects against H₂O₂-induced neurotoxicity.

Neuroglobin (Ngb), so named after its initial discovery in brain neurones, has received great attention as a result of its neuroprotective effects both in vitro and in vivo. Recently, we demonstrated that, in neurones, Ngb is a 17β-oestradiol (E(2) ) inducible protein that is pivotal for hormone-induced anti-apoptotic effects against H(2) O(2) toxicity. The involvement of Ngb in other brain cell populations, as well as in other neuroprotective effects of E(2) , is completely unknown at present. We demonstrate Ngb immunoreactivity in reactive astrocytes located in the proximity of a penetrating cortical injury in vivo and the involvement of Ngb in the E(2) -mediated anti-inflammatory effect in primary cortical astrocytes. Upon binding to oestrogen receptor (ER)β, E(2) enhances Ngb levels in a dose-dependent manner. Although with a lesser degree than E(2) , the pro-inflammatory stimulation with lipopolysaccharide (LPS) also induces the increase of Ngb protein levels via nuclear factor-(NF)κB signal(s). Moreover, a negative cross-talk between ER subtypes and NFκB signal(s) has been demonstrated. In particular, ERα-activated signals prevent the NFκB-mediated Ngb increase, whereas LPS impairs the ERβ-induced up-regulation of Ngb. Therefore, the co-expression of both ERα and ERβ is pivotal for mediating E(2) -induced Ngb expression in the presence of NFκB-activated signals. Interestingly, Ngb silencing prevents the effect of E(2) on the expression of inflammatory markers (i.e. interleukin 6 and interferon γ-inducible protein 10). Ngb can be regarded as a key mediator of the different protective effects of E(2) in the brain, including protection against oxidative stress and the control of inflammation, both of which are at the root of several neurodegenerative diseases.

Several brain disorders associated with neuroinflammation show sex differences in their incidence, onset, progression and/or outcome. The different regulation of the neuroinflammatory response in males and females could underlie these sex differences. In this study, we have explored whether reactive gliosis after a penetrating cortical injury exhibits sex differences. Males presented a higher density of Iba1 immunoreactive cells in the proximity of the wound (0–220 μm) than females. This sex difference was due to a higher number of Iba1 immunoreactive cells with nonreactive morphology. In addition microglia/macrophages in that region expressed arginase‐1, marker of alternatively activated microglia, and the neuroprotective protein Neuroglobin, in a greater proportion in males than in females. No sex differences were found in the number of astrocytes around the lesion. However, the percentage of astrocytes expressing chemokine (C‐C motif) ligand 2 (CCL2), involved in recruitment of immune cells and gliosis regulation, was higher in males. Males also presented a significantly higher density of neurons in the lesion edge than females. These findings indicate that male and female mice have different neuroinflammatory responses after a cortical stab wound injury and suggest that sex differences in reactive gliosis may contribute to sex differences in neuroinflammatory diseases. GLIA 2015;63:1966–1981

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Selective estrogen receptor modulators (SERMs), used for the treatment of breast cancer, osteoporosis, and menopausal symptoms, affect the nervous system. Some SERMs trigger neuroprotective mechanisms and reduce neural damage in different experimental models of neural trauma, brain inflammation, neurodegenerative diseases, cognitive impairment, and affective disorders. New SERMs with specific actions on neurons and glial cells may represent promising therapeutic tools for the brain.