Neuroinflammation comprises a feature of many
neurological disorders that is accompanied by the activation of glial cells and the release of pro-inflammatory
cytokines and
chemokines. Such activation is a normal response oriented to protect neural tissue and it is mainly regulated by microglia and astroglia. However, excessive and chronic activation of glia may lead to neurotoxicity and may be harmful for neural tissue. The ovarian
hormone oestradiol exerts protective actions in the central nervous system that, at least in part, are mediated by a reduction of reactive
gliosis. Several selective oestrogen receptor modulators may also exert
neuroprotective effects by controlling glial inflammatory responses. Thus,
tamoxifen and
raloxifene decrease the inflammatory response caused by
lipopolysaccharide, a bacterial
endotoxin, in mouse and rat microglia cells in vitro.
Tamoxifen and
raloxifene are also able to reduce microglia activation in the brain of male and female rats in vivo after the peripheral administration of
lipopolysaccharide. In addition,
tamoxifen decreases the microglia inflammatory response induced by irradiation. Furthermore, treatment with
tamoxifen and
raloxifene resulted in a significant reduction of the number of reactive astrocytes in the hippocampus of young, middle-aged and older female rats after a
stab wound injury.
Tamoxifen,
raloxifene and the new selective oestrogen receptor modulators
ospemifene and
bazedoxifene decrease the expression and release of interleukine-6 and
interferon-γ inducible protein-10 in cultured astrocytes exposed to
lipopolysaccharide.
Ospemifene and
bazedoxifene exert anti-inflammatory effects in astrocytes by a mechanism involving classical oestrogen receptors and the inhibition of
nuclear factor-kappa B p65 transactivation. These data suggest that oestrogenic compounds are candidates to counteract
brain inflammation under neurodegenerative conditions by targeting the production and release of pro-inflammatory molecules by glial cells.