Estrogen replacement therapy-induced neuroprotection against brain ischemia-reperfusion injury involves the activation of astrocytes via estrogen receptor β.

Yulong Ma,Hailong Dong,Liang Tao,Yan Li,Zhaoyu Liu,Anqi Yin,Lixia Zhang,Lize Xiong,Hang Guo,Wugang Hou

doi:10.1038/srep21467

Abstract

The incidence of ischemic stroke is significantly increased in postmenopausal women. However, the neuroprotective effects of estrogen replacement therapy (ERT) against stroke remain controversial, and the role of astrocytes in ERT has rarely been explored. In this study, we investigated the effects of estrogen and selective estrogen receptor (ER) agonists on astrocytes activation and neuronal apoptosis in mice under conditions of cell culture oxygen and glucose deprivation and reperfusion (OGD-R), and global cerebral ischemia (GCI). We demonstrated that hippocampal astrocytes primarily express ERβ. In astrocytes, 2.5–20 nM 17β-estradiol (E2) or 10 nM DPN (ERβ agonist) not 10 nM PPT (ERα agonist), significantly increased GFAP expression. And 10 nM E2, DPN or E2+MPP (ERα antagonist), but not PPT or E2+PHTPP (ERβ antagonist), significantly reduced neuronal apoptosis following the subjection of astrocyte and neuronal cocultures to OGD-R. We also found that either 50 μg/kg E2 or 8 mg/kg DPN replacement (3 weeks) significantly increased GFAP expression and reduced GCI-induced neuronal apoptosis in hippocampal CA1 region of ovariectomized mice. These results indicate that estrogen-induced neuroprotection against ischemia-reperfusion injury involves activation of astrocytes via ERβ. Thus, the discovery and design of astrocyte-selective ERβ modulators may offer a new strategy for ERT of ischemic stroke.

Highlights

Astrocytes are considered important regulators of the survival and death of neurons and have been recognized as a new target for the prevention of ischemic stroke[9]
The present study aims to explore the role of astrocytes in long-term estrogen replacement therapy (ERT)-induced neuroprotection against ischemic stroke and the underlying molecular mechanism, which may provide a new strategy for ERT for ischemic stroke
In the hippocampus of adult normal female mice (Fig. 1A) and OVX mice (Fig. 1B), we found that ERα primarily colocalized with the neuronal marker Neun, whereas ERβ primarily colocalized with the astrocyte marker glial fibrillary acidic protein (GFAP)

Summary

Introduction

Astrocytes are considered important regulators of the survival and death of neurons and have been recognized as a new target for the prevention of ischemic stroke[9]. Previous studies have found that both ERα and ERβ are expressed in primary cultured and brain tissue astrocytes[11,12]. Astrocytes have the greatest potential to mediate the neuroprotective effects of estrogen. The definitive role of astrocytes in ERT remains unclear. The role of astrocyte ERβ in ERT-induced neuroprotection is poorly understood. A recent study found that ischemic preconditioning-induced brain ischemic tolerance involved the activation of astrocytes[15]. Whether ERT-induced neuroprotection involves the activation of astrocytes has not been thoroughly examined. The present study aims to explore the role of astrocytes in long-term ERT-induced neuroprotection against ischemic stroke and the underlying molecular mechanism, which may provide a new strategy for ERT for ischemic stroke

Methods

Results

Conclusion