Selective oestrogen receptor (ER) modulators reduce microglia reactivity in vivo after peripheral inflammation: potential role of microglial ERs

Abstract

It has been previously reported that the neuroprotective hormone oestradiol reduces microglia inflammatory activity. The objective of this study was to test whether two selective oestrogen receptor modulators, tamoxifen and raloxifene, modulate in vivo the activation of microglia induced by the peripheral administration of lipopolysaccharide (LPS). Activation of microglia was assessed in the white matter of the cerebellum using immunoreactivity for major histocompatability complex-II. Oestradiol, tamoxifen and raloxifene decreased microglia activation induced by LPS in male and ovariectomized female rats, although the doses of oestradiol that were effective in decreasing microglia reactivity were not the same in both sexes. Tamoxifen reduced microglia activation in all experimental groups at all doses tested (0 . 5-2 mg/kg b.w.) while raloxifene lost its anti-inflammatory activity at the higher dose tested (2 mg/kg b.w). In addition, raloxifene had per se a moderate pro-inflammatory activity in the brain of control female rats and its antiinflammatory activity was partially impaired in female animals after 1 month of deprivation of ovarian hormones. Spots of oestrogen receptor (ER)-a immunoreactivity were detected in the soma and cell processes of microglia. Treatment with LPS, oestradiol or tamoxifen induced an increase of ER-a immunoreactive spots in the perikaryon of microglia, while oestradiol antagonized the effect of LPS. The results indicate that some oestrogenic compounds decrease brain inflammation by a mechanism that may involve ERs expressed by microglia. The findings support the potential therapeutic role of oestrogenic compounds as protective anti-inflammatory agents for the central nervous system.

Immunohistochemical evidence for the relationship between microglia and GnRH neurons in the preoptic area of ovariectomized rats with and without steroid replacement

“…Although we have not performed a precise quantitative analysis of the expression intensity of COX-1, the cellular distribution was indistinguishable between different hormonal conditions, at least at the microscopic level. Microglia in some other regions, including the hippocampus and the cerebellum, have been shown to contain α estrogen receptors [24,25], but in microglia in the POA, the estrogen receptor immunoreactivity was not detected in our preliminary experiment. At present, therefore, we do not have evidence for estrogenic influence on COX-1 expression in the glial cells around GnRH neurons.…”

Glial cells and energy balance

“…The number and morphology of microglia in some brain areas are reported to be different between the sexes (Schwarz et al 2012). Although there is little information regarding whether these cells respond differently to metabolic challenges in males and females, estradiol is known to reduce microglia reactivity (Baker et al 2004, Tapia-Gonzalez et al 2008 and decrease the secretion of inflammatory cytokines in astrocytes (Cerciat et al 2010, Rubio et al 2011. Moreover, estrogens and progesterone can block inflammatory cytokine secretion by microglial cells, promoting an antiinflammatory state (Habib et al 2013, Lei et al 2014.…”

Selective estrogen receptor modulators as brain therapeutic agents

“…Tamoxifen and raloxifene are able to decrease the inflammatory response caused by lipopolysaccharide (LPS) in mouse and rat microglia cells in vitro (Suuronen et al 2005). In addition, these SERMs, at doses within the range used in clinical practice, reduce microglia activation in the central nervous system of male and female rats in vivo after the peripheral administration of LPS (Tapia-Gonzalez et al 2008). Figure 3 shows the effect of tamoxifen and raloxifene on microglia activation induced by the systemic administration of LPS.…”