Article

Anti-inflammatory effect of selective estrogen receptor modulators (SERMs) in microglial cells.

Department of Neuroscience and Neurology, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland.
Inflammation Research (Impact Factor: 2.14). 06/2005; 54(5):194-203. DOI: 10.1007/s00011-005-1343-z
Source: PubMed

ABSTRACT Our aim was to study how different SERMs modulate the inflammatory responses induced by lipopolysaccharide (LPS) or unmethylated CpG-oligonucleotides in mouse and rat microglial cells.
Inflammatory responses of mouse N9 microglial cells and rat primary hippocampal microglia to lipopolysaccharide (LPS) exposure were recorded by the secretion of nitric oxide (NO) and cytokine IL-6 in two models where SERM was added either 24 h before LPS addition or simultaneously or even after the LPS exposure. The responses of 17beta-estradiol, tamoxifen, raloxifene and ICI 182.780 were compared. Responses were recorded by ELISA, Northern and EMSA assays.
SERMs but not 17beta-estradiol induced a significant, concentration-dependent anti-inflammatory response both in rat primary microglial cells and in mouse N9 microglial cells. The response was observed both in NO and IL-6 secretion as well as in total IL-6 mRNA expression. We have recently observed that histone deacetylase (HDAC) inhibitors can potentiate the LPS-induced inflammatory response. Raloxifene and tamoxifen inhibited the potentiation of LPS response induced by trichostatin A, an HDAC inhibitor, in N9 microglia. A SERM-induced anti-inflammatory response was observed in acute models where SERM was added simultaneously or even up to 6 h later than LPS exposure. In contrast, the pretreatment of N9 microglia with tamoxifen or raloxifene for 30 h before LPS exposure did not provide any protection against the LPS response. We also observed that the raloxifene-induced protection in N9 microglia was connected to a decline of LPS-induced DNA binding activity of AP-1 but not that of NF-kappaB transcription factors.
Our results show that tamoxifen, raloxifene and ICI 182.780 induce an anti-inflammatory response in acute models of mouse and rat microglial cells. It seems that this response is not estrogen receptor-mediated but, probably, is attributable to some SERM-induced modulation of LPS-activated pro-inflammatory signalling cascades.

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    • "Several studies have shown that some synthetic SERMs, such as tamoxifen, raloxifene, or bazedoxifene [6–29], some nonfeminizing estrogens [30– 34], and some natural SERMs, such as genistein [35] [36], are neuroprotective in vitro and in vivo. The neuroprotective effects of SERMs are associated with a decrease in the activation of microglia and astroglia and a reduction in brain inflammation [37] [38] [39] [40] [41] [42] [43]. In addition, some SERMs have shown to induce neuritic outgrowth in vitro [44] [45], suggesting that these molecules may also affect synaptic connectivity in vivo. "
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    • "Microglial cells are specialized macrophages of the brain that are activated by neuronal injury and are involved, directly or indirectly, in most neurological disorders. Several estrogenic compounds, including the SERMs tamoxifen and raloxifene, reduce microglia activation and the production of inflammatory mediators by microglia in response to various inflammatory stimuli and in animal models of Alzheimer's disease (Drew and Chavis, 2000; Suuronen et al., 2005; Tapia-Gonzalez et al., 2008; Vegeto et al., 2006, 2008). "
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    ABSTRACT: Decreasing levels of sex hormones with aging may have a negative impact on brain function, since this decrease is associated with the progression of neurodegenerative disorders, increased depressive symptoms and other psychological disturbances. Extensive evidence from animal studies indicates that sex steroids, in particular estradiol, are neuroprotective. However, the potential benefits of estradiol therapy for the brain are counterbalanced by negative, life-threatening risks in the periphery. A potential therapeutic alternative to promote neuroprotection is the use of selective estrogen receptor modulators (SERMs), which may be designed to act with tissue selectivity as estrogen receptor agonists in the brain and not in other organs. Currently available SERMs act not only with tissue selectivity, but also with cellular selectivity within the brain and differentially modulate the activation of microglia, astroglia and neurons. Finally, SERMs may promote the interaction of estrogen receptors with the neuroprotective signaling of growth factors, such as the phosphatidylinositol 3-kinase/glycogen synthase kinase 3 pathway.
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    • "Recent studies highlight such a distinguished role for estrogen and, to some extent, for progesterone [23] [95] [96] [185]. For al long time, microglial cells were exclusively or primarily regarded as anti-inflammatory targets for steroids [126] [167] [185]. This view has to be revised, and astrocytes need to be included into the concept of steroid-mediated attenuation of brain inflammation as well. "
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