英國倫敦國王學院研究人員最近在美國《國家科學院學報》上發(fā)表論文稱,，壓力與抑郁癥之間的關聯(lián)源于大腦皮質醇（一種應激激素）的負面效應，而抑制SGK1蛋白水平,，能夠有效地阻斷這一效應,。這一研究發(fā)現(xiàn)為抑郁癥治療新藥的研發(fā)開辟了一條新途徑,。
長期飽受壓力，很可能會導致抑郁癥,，這一關聯(lián)背后的詳細機制目前仍不為科學家所全面理解,。據(jù)世界衛(wèi)生組織估計，到2030年，抑郁癥將成為全球最主要的疾病負擔,，而目前最好的抗抑郁藥物的有效率也僅在50%到65%之間,，開發(fā)新的、更有效的抑郁癥治療藥物迫在眉睫,。無論是抑郁癥,，還是抗抑郁藥物，都與“神經(jīng)形成”,，即大腦不斷生產(chǎn)新的腦細胞這一能力有關,。當人飽受壓力時，大腦皮質醇的水平會增高,，而皮質醇會作用于糖皮質激素受體,，降低大腦的神經(jīng)形成能力，導致新生腦細胞減少,。
在該項研究中,，國王學院的研究人員通過對大腦海馬體干細胞的研究發(fā)現(xiàn)，一種名為SGK1的蛋白對于調節(jié)皮質醇對神經(jīng)形成的影響以及糖皮質激素受體行為具有重要作用,。該蛋白水平增加,，會增強皮質醇的負面效應，使得糖皮質激素受體長期保持活躍狀態(tài),，即使該激素被清除出細胞,，糖皮質激素受體的活躍狀態(tài)依然會保持很長時間，進而大大降低了大腦的神經(jīng)形成能力,。通過實驗,，研究人員使用抑制SGK1蛋白的化合物（GSK650394），成功阻斷了應激激素的負面效應,，最終使新生腦細胞的數(shù)量得以增加,。而通過動物模型和25位抑郁癥患者的血液樣本研究，研究人員最終證實了這一發(fā)現(xiàn),。
該論文第一作者,、倫敦國王學院的克里斯托弗·阿納克爾博士指出，神經(jīng)形成能力下降被認為是導致抑郁癥的重要因素,，因此以調節(jié)這一過程的分子通路為標靶是一個潛在的抑郁癥治療方向,。新發(fā)現(xiàn)對于理解壓力對情緒的影響以至抑郁癥的形成都十分重要，而未來通過藥物降低病患體內SGK1蛋白水平可能會成為抑郁癥治療的一個有效手段,。（生物谷Bioon.com）
生物谷推薦英文摘要：
PNAS doi:10.1073/pnas.1300886110
Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis
Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms mediating these effects are poorly understood. Here we identify the glucocorticoid receptor (GR) target gene, serum- and glucocorticoid-inducible kinase 1 (SGK1), as one such mechanism. Using a human hippocampal progenitor cell line, we found that a small molecule inhibitor for SGK1, GSK650394, counteracted the cortisol-induced reduction in neurogenesis. Moreover, gene expression and pathway analysis showed that inhibition of the neurogenic Hedgehog pathway by cortisol was SGK1-dependent. SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation. Experiments combining the inhibitor for SGK1, GSK650394, with the GR antagonist, RU486, demonstrated that SGK1 was involved in the cortisol-induced reduction in progenitor proliferation both downstream of GR, by regulating relevant target genes, and upstream of GR, by increasing GR function. Corroborating the relevance of these findings in clinical and rodent settings, we also observed a significant increase of SGK1 mRNA in peripheral blood of drug-free depressed patients, as well as in the hippocampus of rats subjected to either unpredictable chronic mild stress or prenatal stress. Our findings identify SGK1 as a mediator for the effects of cortisol on neurogenesis and GR function, with particular relevance to stress and depression.
