Anti-inflammatory effect of selective estrogen receptor modulators (SERMSs) in microglial cells
Department of Neuroscience and Neurology, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland. Inflammation Research
(Impact Factor: 2.35).
06/2005; 54(5):194-203. DOI: 10.1007/s00011-005-1343-z
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.
Available from: George E. Barreto
- "Interestingly, some unpublished data from our lab demonstrate that reactive microglia is reduced in young animals treated with 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) (estrogen receptor beta agonist; 93.95 ± 2.41), 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) (68.99 ± 6.42) and combined DPN+PPT (52.99 ± 2.23) in comparison to controls (184.28 ± 15.59), suggesting that both receptors may be mediating these protective effects in our model. Besides SERMs effects on microglia activation (Suuronen et al., 2005; Tapia-Gonzalez et al., 2008; Liu et al., 2010; Arevalo et al., 2012), previous studies also showed that raloxifene and tamoxifen induced upregulation of glutamate transporters (Karki et al., 2014), potentiation of mitochondrial superoxide dismutase (Wakade et al., 2008), improves functional outcome following spinal cord injury (Tian et al., 2009), and reduces inflammation via estrogen receptor beta (Baker et al., 2004). Since traumatic brain injury induces a complex cascade of events, which involves increased production of pro-inflammatory molecules, activating microglia, thus augmenting tissue damage and neuronal death, SERMs may act by decreasing the production of inflammatory cytokines secreted by microglia and improve the outcome in both aged and young subjects. "
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ABSTRACT: Following brain injury, microglia assume a reactive-like state and secrete pro-inflammatory molecules that can potentiate damage. A therapeutic strategy that may limit microgliosis is of potential interest. In this context, selective estrogen receptor modulators, such as raloxifene and tamoxifen, are known to reduce microglia activation induced by neuroinflammatory stimuli in young animals. In the present study, we have assessed whether raloxifene and tamoxifen are able to affect microglia activation after brain injury in young and aged animals in time points relevant to clinics, which is hours after brain trauma. Volume fraction of MHC-II(+) microglia was estimated according to the point-counting method of Weibel within a distance of 350 μm from the lateral border of the wound, and cellular morphology was measured by fractal analysis. Two groups of animals were studied: (1) young rats, ovariectomized at 2 months of age; and (2) aged rats, ovariectomized at 18 months of age. Fifteen days after ovariectomy animals received a stab wound brain injury and the treatment with estrogenic compounds. Our findings indicate that raloxifene and tamoxifen reduced microglia activation in both young and aged animals. Although the volume fraction of reactive microglia was found lower in aged animals, this was accompanied by important changes in cell morphology, where aged microglia assume a bushier and hyperplasic aspect when compared to young microglia. These data suggest that early regulation of microglia activation provides a mechanism by which selective estrogen receptors modulators (SERMs) may exert a neuroprotective effect in the setting of a brain trauma.
Frontiers in Aging Neuroscience 07/2014; 6:132. DOI:10.3389/fnagi.2014.00132 · 4.00 Impact Factor
Available from: PubMed Central
- "Several previous reports from experimental studies have demonstrated that tamoxifen plays neuroprotective roles in spinal cord injury , intracerebral hemorrhage , brain ischemia , and hypoxic-ischemic brain injury . At the same time, previous studies have proven that tamoxifen could induce an anti-inflammatory response in acute models of mouse and rat microglial cells; this response seemed not to be estrogen receptor-mediated but probably was attributable to some tamoxifen-induced modulation of pro-inflammatory signaling cascades [11,12]. "
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ABSTRACT: Tamoxifen, a selective estrogen receptor modulator, has successfully been used to treat several animal models of brain injury, but the underlying mechanisms remain unclear. This study was undertaken to evaluate the effect of tamoxifen on the toll-like receptor 4 (TLR4)- and nuclear factor-kappaB (NF-kappaB)-related inflammatory signaling pathway and secondary brain injury in rats after subarachnoid hemorrhage (SAH).
Adult male Sprague-Dawley rats were divided into four groups: (1) control group (n = 28); (2) SAH group (n = 28); (3) SAH + vehicle group (n = 28); and (4) SAH + tamoxifen group (n = 28). All SAH animals were subjected to injection of autologous blood into the prechiasmatic cistern once on day 0. In SAH + tamoxifen group, tamoxifen was administered intraperitoneally at a dose of 5 mg/kg at 2 h, 12 h, and 36 h after SAH. In the first set of experiments, brain samples were extracted and evaluated at 48 h after SAH. In the second set of experiments, the Morris water maze was used to investigate cognitive and memory changes.
We found that treatment with tamoxifen markedly inhibited the protein expressions of TLR4, NF-kappaB and the downstream inflammatory agents, such as interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and intercellular adhesion molecule-1 (ICAM-1). Administration of tamoxifen following SAH significantly ameliorated the early brain injury (EBI), such as brain edema, blood-brain barrier (BBB) impairment, and clinical behavior scale. Learning deficits induced by SAH were markedly alleviated after tamoxifen treatment.
Post-SAH tamoxifen administration may attenuate TLR4/NF-kappaB-mediated inflammatory response in the rat brain and result in abatement of the development of EBI and cognitive dysfunction after SAH.
Journal of Neuroinflammation 12/2013; 10(1):157. DOI:10.1186/1742-2094-10-157 · 5.41 Impact Factor
Available from: Dulce Anahí Velázquez-Zamora
- "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  , 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       . In addition, some SERMs have shown to induce neuritic outgrowth in vitro  , suggesting that these molecules may also affect synaptic connectivity in vivo. "
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ABSTRACT: Some selective estrogen receptor modulators, such as raloxifene and tamoxifen, are neuroprotective and reduce brain inflammation in several experimental models of neurodegeneration. In addition, raloxifene and tamoxifen counteract cognitive deficits caused by gonadal hormone deprivation in male rats. In this study, we have explored whether raloxifene and tamoxifen may regulate the number and geometry of dendritic spines in CA1 pyramidal neurons of the rat hippocampus. Young adult male rats were injected with raloxifene (1 mg/kg), tamoxifen (1 mg/kg), or vehicle and killed 24 h after the injection. Animals treated with raloxifene or tamoxifen showed an increased numerical density of dendritic spines in CA1 pyramidal neurons compared to animals treated with vehicle. Raloxifene and tamoxifen had also specific effects in the morphology of spines. These findings suggest that raloxifene and tamoxifen may influence the processing of information by hippocampal pyramidal neurons by affecting the number and shape of dendritic spines.
Neural Plasticity 01/2012; 2012(2):309494. DOI:10.1155/2012/309494 · 3.58 Impact Factor
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