Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands.
CAS Key Laboratory of Brain Function and Diseases, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, P. R. China.
Brain Pathol. 2018 Jul;28(4):536-547. doi: 10.1111/bpa.12548. Epub 2017 Aug 17.
Altered levels of steroids have been reported in the brain, cerebral spinal fluid and plasma of patients with mood disorders. Neuroimaging studies have reported both functional and structural alterations in mood disorders, for instance in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC). In order to determine whether the endogenous production of steroids is altered in the ACC and DLPFC of patients with major depressive disorder (MDD) or bipolar disorder (BPD), quantitative real-time PCR was performed to detect mRNA expression level of key enzymes in the steroid biosynthetic pathways. In MDD, a significant decrease in mRNA level of cytochrome P450 17A1 (CYP17A1, synthesizing C19 ketosteroids) in the ACC and a significant increase in mRNA levels of hydroxysteroid sulfotransferase 2A1 [SULT2A1, catalyzing the sulfate conjugation of dehydroepiandrosterone (DHEA)] were observed in the DLPFC, suggesting alterations in DHEA and its sulfate metabolite DHEAS levels. Decreased intensity and distribution of CYP17A1 immunohistochemical staining was found in the ACC of MDD patients. Interestingly, there was a significant positive correlation between the mRNA levels of CYP17A1 and tyrosine-related kinase B (TrkB) full length isoform. In a unique post-mortem human brain slice culture paradigm, BDNF mRNA expression was found to be significantly increased following incubation with DHEA. Together, these data indicate a close relationship between DHEA and BDNF-TrkB pathways in depression. Furthermore, in the DLPFC, higher mRNA levels of 11β-hydroxysteroid dehydrogenase-1 (HSD11B1, reducing cortisone to the active hormone cortisol) and steroidogenic acute regulatory protein (STAR, facilitating the shuttle of cholesterol through the intermembrane space) were found in the MDD patients and BPD patients, respectively. In conclusion, this study suggests the presence of a disturbance in the endogenous synthesis of DHEA and DHEAS in mood disorders, which has a close relationship with BDNF-TrkB signaling.
已有报道称，情绪障碍患者的大脑、脑脊液和血浆中的类固醇水平发生了改变。神经影像学研究报告称，情绪障碍患者的前扣带皮层（ACC）和背外侧前额叶皮层（DLPFC）存在功能和结构改变。为了确定重度抑郁症（MDD）或双相情感障碍（BPD）患者的 ACC 和 DLPFC 中类固醇的内源性产生是否发生改变，采用定量实时 PCR 检测了类固醇生物合成途径中关键酶的 mRNA 表达水平。在 MDD 中，ACC 中细胞色素 P450 17A1（CYP17A1，合成 C19 酮类固醇）的 mRNA 水平显著降低，而 DLPFC 中羟甾体硫酸转移酶 2A1 [SULT2A1，催化脱氢表雄酮（DHEA）的硫酸结合]的 mRNA 水平显著升高，表明 DHEA 及其硫酸盐代谢物 DHEAS 水平发生改变。在 MDD 患者的 ACC 中发现 CYP17A1 免疫组化染色强度和分布减少。有趣的是，CYP17A1 的 mRNA 水平与酪氨酸相关激酶 B（TrkB）全长异构体之间存在显著正相关。在独特的死后人脑切片培养范式中，发现 BDNF mRNA 表达在与 DHEA 孵育后显著增加。总之，这些数据表明 DHEA 和 BDNF-TrkB 通路在抑郁症中密切相关。此外，在 DLPFC 中，MDD 患者和 BPD 患者的 11β-羟类固醇脱氢酶-1（HSD11B1，将考的松还原为活性激素皮质醇）和类固醇急性调节蛋白（STAR，促进胆固醇穿过膜间空间的穿梭）的 mRNA 水平分别升高。总之，本研究表明情绪障碍中存在 DHEA 和 DHEAS 内源性合成紊乱，与 BDNF-TrkB 信号密切相关。
