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

Ma Y, Guo H, Zhang L, Tao L, Yin A, Liu Z, Li Y, Dong H, Xiong L, Hou W - Sci Rep (2016)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.

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.

No MeSH data available.


Related in: MedlinePlus

Pre-treatment with E2 and DPN decreased cleaved-Caspase-3 protein expression in neurons received OGD and reperfusion (n = 5).(A) Data are shown as the mean ± S.D; *p < 0.05 and **p < 0.01 vs. Con group. (B) Cropped gels and blots showing the expression of cleaved-Caspase-3 protein in Con, 10 nM E2 or 10 nM DPN group. The samples derive from the same experiment and that gels/blots were processed in parallel. Full-length blots/gels are presented in Supplementary Fig. 4.
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f9: Pre-treatment with E2 and DPN decreased cleaved-Caspase-3 protein expression in neurons received OGD and reperfusion (n = 5).(A) Data are shown as the mean ± S.D; *p < 0.05 and **p < 0.01 vs. Con group. (B) Cropped gels and blots showing the expression of cleaved-Caspase-3 protein in Con, 10 nM E2 or 10 nM DPN group. The samples derive from the same experiment and that gels/blots were processed in parallel. Full-length blots/gels are presented in Supplementary Fig. 4.

Mentions: Next, we detected the effects of estrogen and DPN on the expression of cleaved-Caspase-3 protein, which is an apoptosis marker. The results analyzed by immunofluorescence and western blot assays corresponded to those of the flow cytometric analysis. As shown in Fig. 8, an immunofluorescence assay indicated that the proportion of cleaved-Caspase-3-positive cells was 55.0% ± 2.9% in the Con group. Pretreatment with 10 nM E2 or 10 nM DPN significantly decreased the proportions of cleaved-Caspase-3-positive cells to 33.7% ± 3.5% and 43.0% ± 2.9%, respectively (#p < 0.05, ##p < 0.01 vs. the Con group). No significant difference was observed between the 10 nM E2 group and the 10 nM DPN group. Western blot analysis (Fig. 9) confirmed that pretreatment with 10 nM E2 or 10 nM DPN significantly decreased the expression levels of cleaved-Caspase-3 protein compared with that of the Con group (*p < 0.05 and **p < 0.01). No significant difference was observed between the 10 nM E2 group and the 10 nM DPN group.


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

Ma Y, Guo H, Zhang L, Tao L, Yin A, Liu Z, Li Y, Dong H, Xiong L, Hou W - Sci Rep (2016)

Pre-treatment with E2 and DPN decreased cleaved-Caspase-3 protein expression in neurons received OGD and reperfusion (n = 5).(A) Data are shown as the mean ± S.D; *p < 0.05 and **p < 0.01 vs. Con group. (B) Cropped gels and blots showing the expression of cleaved-Caspase-3 protein in Con, 10 nM E2 or 10 nM DPN group. The samples derive from the same experiment and that gels/blots were processed in parallel. Full-length blots/gels are presented in Supplementary Fig. 4.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4759820&req=5

f9: Pre-treatment with E2 and DPN decreased cleaved-Caspase-3 protein expression in neurons received OGD and reperfusion (n = 5).(A) Data are shown as the mean ± S.D; *p < 0.05 and **p < 0.01 vs. Con group. (B) Cropped gels and blots showing the expression of cleaved-Caspase-3 protein in Con, 10 nM E2 or 10 nM DPN group. The samples derive from the same experiment and that gels/blots were processed in parallel. Full-length blots/gels are presented in Supplementary Fig. 4.
Mentions: Next, we detected the effects of estrogen and DPN on the expression of cleaved-Caspase-3 protein, which is an apoptosis marker. The results analyzed by immunofluorescence and western blot assays corresponded to those of the flow cytometric analysis. As shown in Fig. 8, an immunofluorescence assay indicated that the proportion of cleaved-Caspase-3-positive cells was 55.0% ± 2.9% in the Con group. Pretreatment with 10 nM E2 or 10 nM DPN significantly decreased the proportions of cleaved-Caspase-3-positive cells to 33.7% ± 3.5% and 43.0% ± 2.9%, respectively (#p < 0.05, ##p < 0.01 vs. the Con group). No significant difference was observed between the 10 nM E2 group and the 10 nM DPN group. Western blot analysis (Fig. 9) confirmed that pretreatment with 10 nM E2 or 10 nM DPN significantly decreased the expression levels of cleaved-Caspase-3 protein compared with that of the Con group (*p < 0.05 and **p < 0.01). No significant difference was observed between the 10 nM E2 group and the 10 nM DPN group.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.

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.

No MeSH data available.


Related in: MedlinePlus