双向障碍中糖皮质激素对下丘脑-垂体-肾上腺轴活性的负反馈调节

Negative feedback regulation of hypothalamic-pituitary-adrenal axis activity by glucocorticoid in bipolar disorder

摘要:

双相障碍（bipolar disorder，BD）是心境障碍（mood disorders）的一个主要亚型，心境障碍的另外一个重要亚型是重性抑郁障碍（major depressive disorder，MDD），也称单相抑郁。BD具有躁狂和抑郁2大证候群，并呈现周期性循环。和MDD一样，BD也是严重损害人类精神健康的重大疾病。体内应激反应系统例如下丘脑-垂体-肾上腺（hypothalamic-pituitary-adrenal，HPA）轴活性紊乱已经大量研究证实是心境障碍的重要发病机制。但是，目前还缺乏系统地针对BD患者HPA轴活性的研究。现有的大部分研究仅仅关注BD患者血浆水平或者唾液皮质醇水平的改变，并且研究结果存在很大差异。但是，地塞米松/促肾上腺皮质激素释放激素（DEX/CRH）抑制试验的结果却比较一致：皮质醇抑制显著减弱，这个结论表明BD患者中HPA轴的负反馈调节功能发生异常。HPA轴的负反馈调节中，糖皮质激素受体（glucocorticoid receptor，GR）和免疫亲和素（immunophilin）家族蛋白之一， FK506结合蛋白51（FK 506 binding protein 51，FKBP51）是2个重要的分子。一方面，GR基因单核苷酸多态性被认为与BD发病相关。另一方面，童年期创伤经历导致BD发病风险增加的机制被推测是通过影响HPA轴敏感性实现的，而在这一过程中，GR和FKBP51参与了对HPA轴敏感性的调节。本综述将对近年来针对BD患者HPA轴活性异常的研究及其和GR和FKBP51导致的HPA轴负反馈调节紊乱的研究总结分析，旨在为BD与应激反应相关的发病机制研究提供新的思路。

Abstract:

Bipolar disorder (BD) is a major subtype of mood disorders, and major depressive disorder (MDD), also called unipolar depression, is another important subtype of mood disorders. BD is characterized by cyclical alterations of depressive and maniac symptoms. Both BD and MDD are serious diseases which greatly affect human mental health. Dysfunction of stress response systems including the hypothalamic-pituitary-adrenal (HPA) axis has been confirmed to be an important pathogenesis of mood disorders. However, there is still a lack of systematic studies on HPA axis activity in BD patients. Most of the existing studies only focus on the changes in the levels of plasma cortisol and salivary cortisol, with a great difference in results between these studies; however, dexamethasone/corticotropin-releasing hormone test has achieved relatively consistent results from the studies and has shown a significant reduction in cortisol inhibition, suggesting an abnormal negative feedback regulation function of the HPA axis in BD patients. Glucocorticoid receptor (GR) and FK 506 binding protein 51 (FKBP51), a member of the immunophilin family, are two important molecules involved in the negative feedback regulation of the HPA axis. On the one hand, single nucleotide polymorphism of the GR gene is thought to be associated with the onset of BD; on the other hand, childhood trauma may increase the risk of BD, possibly by affecting the sensitivity of the HPA axis, and GR and FKBP51 are involved in the regulation of the sensitivity of the HPA axis during this process. This article reviews the recent studies on abnormal HPA axis activity in BD patients and disorder in negative feedback regulation of the HPA axis caused by GR and FKBP51, in order to provide new ideas for research on the pathogenesis of BD associated with stress response.