Glucocorticoid Receptor β Isoform Predominates in the Human Dysplastic Brain Region and Is Modulated by Age, Sex, and Antiseizure Medication.
Glucocorticoid Receptor β Isoform Predominates in the Human Dysplastic Brain Region and Is Modulated by Age, Sex, and Antiseizure Medication.
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DOI：
10.3390/ijms23094940
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发表时间：
2022-04-29
影响因子：
5.6
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中科院分区：
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血脑屏障糖皮质激素受体(GR)参与了难治性癫痫伴局灶性皮质发育不良的发病机制，但GR亚型GRα和GRβ在发育不良脑中的作用尚不清楚。我们利用来自癫痫切除手术患者的发育不良/癫痫和非发育不良脑组织来确定GRα和GRβ水平、亚细胞定位和细胞特异性。用从发育不良脑组织分离的血脑屏障内皮细胞(EPI-ECs)破译与药物调节和血脑屏障完整性相关的关键血脑屏障蛋白，并与对照组和高表达GRβ的血脑屏障内皮细胞进行比较。与非发育不良组织相比，GRβ在发育不良组织中表达上调，GRα/GRβ比率在女性和男性之间以及45岁的患者中显著失衡。在外周静脉内皮细胞中，GRβ、HSP90、3A4和CYP2C9的亚细胞定位和表达模式与GRβ+脑内皮细胞一致。外周静脉内皮细胞和GRβ+内皮细胞活性基质金属蛋白酶水平和活性升高，而Claudin-5水平降低。综上所述，GRβ对发育不良的血脑屏障功能蛋白有重要影响，并且与年龄和性别有关，提示脑GRβ在异常发育中的关键作用，可作为癫痫的潜在生物标志物和治疗靶点。
The glucocorticoid receptor (GR) at the blood–brain barrier (BBB) is involved in the pathogenesis of drug-resistant epilepsy with focal cortical dysplasia (FCD); however, the roles of GR isoforms GRα and GRβ in the dysplastic brain have not been revealed. We utilized dysplastic/epileptic and non-dysplastic brain tissue from patients who underwent resective epilepsy surgery to identify the GRα and GRβ levels, subcellular localization, and cellular specificity. BBB endothelial cells isolated from the dysplastic brain tissue (EPI-ECs) were used to decipher the key BBB proteins related to drug regulation and BBB integrity compared to control and transfected GRβ-overexpressed BBB endothelial cells. GRβ was upregulated in dysplastic compared to non-dysplastic tissues, and an imbalance of the GRα/GRβ ratio was significant in females vs. males and in patients > 45 years old. In EPI-ECs, the subcellular localization and expression patterns of GRβ, Hsp90, CYP3A4, and CYP2C9 were consistent with GRβ+ brain endothelial cells. Active matrix metalloproteinase levels and activity increased, whereas claudin-5 levels decreased in both EPI-ECs and GRβ+ endothelial cells. In conclusion, the GRβ has a major effect on dysplastic BBB functional proteins and is age and gender-dependent, suggesting a critical role of brain GRβ in dysplasia as a potential biomarker and therapeutic target in epilepsy.