Koning Anne-Sophie C A M, Habets Philippe C, Bogaards Marit, Kroon Jan, van Santen Hanneke M, de Bont Judith M, Meijer Onno C
Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Endocr Connect. 2022 Mar 14;11(3):e210425. doi: 10.1530/EC-21-0425.
Synthetic glucocorticoids like dexamethasone can cause severe neuropsychiatric effects. They preferentially bind to the glucocorticoid receptor (GR) over the mineralocorticoid receptor (MR). High dosages result in strong GR activation but likely also result in lower MR activation based on GR-mediated negative feedback on cortisol levels. Therefore, reduced MR activity may contribute to dexamethasone-induced neuropsychiatric symptoms.
In this single case study, we evaluate whether dexamethasone leads to reduced MR activation in the human brain. Brain tissue of an 8-year-old brain tumor patient was used, who suffered chronically from dexamethasone-induced neuropsychiatric symptoms and deceased only hours after a high dose of dexamethasone.
The efficacy of dexamethasone to induce MR activity was determined in HEK293T cells using a reporter construct. Subcellular localization of GR and MR was assessed in paraffin-embedded hippocampal tissue from the patient and two controls. In hippocampal tissue from the patient and eight controls, mRNA of MR/GR target genes was measured.
In vitro, dexamethasone stimulated MR with low efficacy and low potency. Immunofluorescence showed the presence of both GR and MR in the hippocampal cell nuclei after dexamethasone exposure. The putative MR target gene JDP2 was consistently expressed at relatively low levels in the dexamethasone-treated brain samples. Gene expression showed substantial variation in MR/GR target gene expression in two different hippocampus tissue blocks from the same patient.
Dexamethasone may induce MR nuclear translocation in the human brain. Conclusions on in vivo effects on gene expression in the brain await the availability of more tissue of dexamethasone-treated patients.
地塞米松等合成糖皮质激素可导致严重的神经精神效应。它们与糖皮质激素受体（GR）的结合优先于盐皮质激素受体（MR）。高剂量会导致强烈的GR激活，但基于GR对皮质醇水平的负反馈，可能也会导致较低的MR激活。因此，MR活性降低可能导致地塞米松诱导的神经精神症状。
在本单病例研究中，我们评估地塞米松是否会导致人脑中MR激活降低。使用了一名8岁脑肿瘤患者的脑组织，该患者长期患有地塞米松诱导的神经精神症状，在高剂量地塞米松治疗后仅数小时死亡。
使用报告构建体在HEK293T细胞中确定地塞米松诱导MR活性的效力。在患者和两名对照的石蜡包埋海马组织中评估GR和MR的亚细胞定位。在患者和八名对照的海马组织中，测量MR/GR靶基因的mRNA。
在体外，地塞米松刺激MR的效力和效能较低。免疫荧光显示地塞米松暴露后海马细胞核中同时存在GR和MR。在经地塞米松处理的脑样本中，假定的MR靶基因JDP2始终以相对较低的水平表达。基因表达显示同一患者的两个不同海马组织块中MR/GR靶基因表达存在显著差异。
地塞米松可能会诱导人脑中MR的核转位。关于其对脑内基因表达的体内效应的结论有待获得更多地塞米松治疗患者的组织。
