Selective activation of estrogen receptor β alleviates cerebral ischemia neuroinflammatory injury

Abstract

The stroke incidence in menopausal women was abruptly increased combining with much worse stoke outcomes. Estrogen replacement therapy has the potential to become a new neuroprotective strategy against stroke. But the adverse oncogenic events extremely limited its clinical application. As estrogen receptor (ER) β is seldom expressed in the female reproductive organs, selective activation of ERβ is a promising alternative therapy. However, the role and mechanism of ERβ in stroke neuroprotection remain largely unknown. In this study, we investigated the effects of activating ERβ on microglia and astrocyte activation and NF-κB mediated neuroinflammatory injury induced by middle cerebral artery occlusion and reperfusion (MCAO-R) or oxygen and glucose deprivation and reperfusion (OGD-R). We found that 8 mg/kg DPN (ERβ-specific agonist) replacement therapy (3 weeks) to the ovariectomized (OVX) mice significantly reduced ischemia injury and alleviated microglia and astrocyte activation, and markedly inhibited the expression of NF-κB and proinflammatory cytokines (TNF-α, IL-1β, and IL-6). Moreover, pretreatment (72 h) with 10 nM DPN to the cell line of microglia (N9) or astrocyte (MA1800) significantly increased the cell viability and decreased the cell apoptosis and damage after OGD-R injury, and significantly inhibited the expression of NF-κB and proinflammatory cytokines. These results concluded that DPN replacement treatment alleviated the cerebral ischemia-reperfusion injury via inhibiting the activation of microglia and astrocyte and NF-κB mediated neruoinflammation. As ERβ agonist have only minor effects in classic estrogen target tissues, we propose that selective activating ERβ is a promising therapy to suppress stroke neuroinflammatory injury in menopausal women.

Keywords: Astrocyte; Cerebral ischemia; Estrogen receptor β (ERβ); Microglia; NF-κB; Neuroinflammation.