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

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 anti-inflammatory activity was partially impaired in female animals after 1 month of deprivation of ovarian hormones. Spots of oestrogen receptor (ER)-alpha immunoreactivity were detected in the soma and cell processes of microglia. Treatment with LPS, oestradiol or tamoxifen induced an increase of ER-M 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.