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17β-estradiol (E2) and progesterone (P) are neuroprotective factors in the brain preventing neuronal death under different injury paradigms. In previous studies, we demonstrated that both steroids dampen neuronal damage, improve local energy metabolism and attenuate pro-inflammatory responses. MicroRNAs (miRNAs) are small regulators of distinct target genes on the RNA level. Their expression patterns are misbalanced in several neurological disorders. To explore the regulatory mechanisms of steroid hormones on selected miRNAs and their validated targets in ischemia, we used the transient middle cerebral artery occlusion (tMCAO) model. 12-week old male rats were subjected to 2 h tMCAO and expression patterns of miR‐223, miR‐200c, miR‐375, miR‐199 and miR‐214 (all −3p) were determined. Using semi-quantitative real time PCR, we examined the role of E2 or P as regulatory factors for miRNAs and theirs target genes. Besides miR-375, all mentioned miRNAs showed a steady increase with a peak at 72 h post tMCAO, whereas highest levels of miR-375 were detected at 12 h post tMCAO. E2 or P selectively dampened miR-223 and miR-214 but further boosted miR-375 levels. With respect to the miR-223 regulated target genes NR2B and GRIA2 which both decreased after tMCAO, E2 and P application reversed this effect. Further, steroid treatment inhibited the hypoxia-induced increase of the miR-375 target genes Bcl-2 and RAD1. These findings provide new insights into the regulatory role of neuroprotection mediated by sex steroids in the brain. Both hormones are capable of influencing the expression of miRNAs which are relevant during neuropathological processes. Thereby, E2 and P indirectly control pro-apoptotic and −inflammatory gene translation and provide a mechanism to dampen explosive tissue damage. [ABSTRACT FROM AUTHOR]

Abstract: Sex steroids are neuroprotective following traumatic brain injury or during neurodegenerative processes. In a recent short-term study, we have shown that 17β-estradiol (E) and progesterone (P) applied directly after ischemia reduced the infarct volume by more than 70%. This protection might primarily result from the anti-inflammatory effects of steroids. Here, we focus on the long-term neuroprotection by both steroids with respect to the infarct volume, functional recovery, and vessel density in the penumbra. The application of E/P during the first 48h after stroke (transient middle cerebral artery occlusion, tMCAO) revealed neuroprotection after two weeks. The infarct area was reduced by 70% and motor activity was preserved compared to placebo-treated animals. Blood vessel density in the penumbra using immunohistochemistry for von Willebrand factor showed increased vessel density after tMCAO which was not affected by hormones. Expression of vascular endothelial growth factor (VEGF) and its receptor (R1) was increased at 24h after tMCAO and up-regulated by E/P but not changed 14 days after stroke. These findings suggest that the neuroprotective potency of both steroids is sustained and persists for at least two weeks. Besides anti-inflammatory and anti-apoptotic actions, angiogenesis in the damaged area appears to be initially affected early after ischemia and is manifested up to two weeks. This article is part of a Special Issue entitled ‘Neurosteroids’. [Copyright &y& Elsevier]

Highlights • Hypoxia impacts on the inflammasome NLRP3/ASC/caspase-1 axis in BV-2 cells and primary astroglia. • Estrogen and progesterone counteracts hypoxia-induced effects on NLRP3 and ASC. • Sex steroids fail to mitigate caspase-1 mediated IL1beta maturation. Abstract Clinical and animal model studies have demonstrated the neuroprotective and anti-inflammatory effects of 17beta-estradiol (E2) and progesterone (P) in different disease models of the central nervous system (CNS) including ischemic stroke. Inflammasomes are involved in the interleukin-1 beta (IL1beta) maturation, in particular, NLRP3, the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) and the active caspase-1 (Casp1) form. Recently, we showed that administration of E2 or P selectively regulated these components after experimental ischemic stroke in rats. Therefore, we investigated the impact of E2 and P on the NLRP3/ASC/Casp1 axis in the murine microglia-like cell line BV-2 cells and primary astrocytes after short-term in vitro hypoxia. The inflammatory cytokine IL1beta but not IL18 was increased after short-term hypoxia in astroglia and BV-2 cells. The same applied to NLPR3 and ASC. Casp1 activity was also elevated in astroglia and BV-2 cells after hypoxia. The administration of E2 or P selectively dampened IL1beta, ASC and NLRP3 expression mainly in BV-2 cells. Both steroid hormones failed to reduce Casp1 activity after hypoxia. We conclude that E2- and P-mediated anti-inflammatory mechanisms occur upstream of Casp1 through the regulation of NLRP3 and its adaptor ASC. [ABSTRACT FROM AUTHOR]

Estrogens modulate the immune system and possess anti-inflammatory properties. In line, immune cells express a variety of estrogen receptors (ER) including ER-alpha and -beta. In the present study, we examined the influence of 17beta-estradiol (E2) serum concentrations on blood leukocyte composition and their ex vivo polarization/activation status by FACS analysis in sub-fertile human females under controlled ovarian stimulation (COS). Using a set of cell-type and polarization-specific markers, we demonstrate that increased 17ß-estradiol (E2) serum concentrations yield an overall increase in leukocytes, neutrophils and monocytes but decreased lymphocytes. There was a clear ratio shift towards an increase in M2 monocytes with a protective quality and an increase in T-helper cells compared to a decrease in cytotoxic T-cells. These data support experimental findings and clinical trials, i.e. related to multiple sclerosis and other autoimmune-related diseases, that have shown a down-regulation of CD8(+) T cells and up-regulation of T-regulatory cells. Further studies have to pinpoint to which extent the immune system/-responsiveness of otherwise healthy female patients is affected by medium-term systemic E2 variations. [ABSTRACT FROM AUTHOR]