Hunsberger Joshua G, Austin Daniel R, Chen Guang, Manji Husseini K
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Brain Res. 2009 Oct 13;1293:76-84. doi: 10.1016/j.brainres.2009.06.103. Epub 2009 Jul 10.
Bipolar disorder (BPD) is a devastating psychiatric illness marked by recurrent episodes of mania and depression. While the underlying pathophysiology of BPD remains elusive, an abnormal hypothalamic-pituitary-adrenal (HPA) axis and dysfunctional glucocorticoid receptor (GR) signaling are considered hallmarks. This review will examine how targeting resiliency signaling cascades at the cellular level may serve as a mechanism to treat BPD. Here, cellular resiliency is defined as the ability of a cell to adapt to an insult or stressor. Such resiliency at the cellular level could confer resiliency at the systems level and, ultimately, help individuals to cope with stressors or recover from depressive or manic states. This review will focus on four molecular targets of mood stabilizers that are known to play integral roles in these cellular resiliency signaling pathways: (1) B-cell CLL/lymphoma 2 (Bcl-2), (2) Bcl-2-associated athanogene (BAG-1), (3) glucocorticoid receptors (GRs), and (4) 51 kDa FK506-binding protein (FKBP5). These targets have emerged from neurobiological and human genetic studies and employ mechanisms that modulate GR function or promote anti-apoptotic processes critical to affective resilience. Future research should focus on elucidating sustainable treatments that target resiliency factors-such as BAG-1 or FKBP5-which could ultimately be used to treat individuals suffering from BPD and prevent relapses in afflicted individuals. Further identification of resiliency and susceptibility factors will also be vital. Ultimately, these developments would allow for the treatment of susceptible individuals prior to the development of BPD.
双相情感障碍（BPD）是一种严重的精神疾病，其特征为躁狂和抑郁反复发作。虽然BPD的潜在病理生理学机制仍不清楚，但下丘脑 - 垂体 - 肾上腺（HPA）轴异常和糖皮质激素受体（GR）信号功能失调被认为是其标志。本综述将探讨在细胞水平上靶向弹性信号级联反应如何可能作为治疗BPD的一种机制。在这里，细胞弹性被定义为细胞适应损伤或应激源的能力。细胞水平上的这种弹性可以在系统水平上赋予弹性，并最终帮助个体应对应激源或从抑郁或躁狂状态中恢复。本综述将聚焦于情绪稳定剂的四个分子靶点，已知它们在这些细胞弹性信号通路中发挥着不可或缺的作用：（1）B细胞淋巴瘤/白血病-2（Bcl-2），（2）Bcl-2相关抗凋亡基因（BAG-1），（3）糖皮质激素受体（GRs），以及（4）51 kDa FK506结合蛋白（FKBP5）。这些靶点来自神经生物学和人类遗传学研究，其作用机制是调节GR功能或促进对情感弹性至关重要的抗凋亡过程。未来的研究应聚焦于阐明针对弹性因子（如BAG-1或FKBP5）的可持续治疗方法，这些方法最终可用于治疗BPD患者并预防患病个体复发。进一步鉴定弹性和易感性因子也将至关重要。最终，这些进展将使易感个体在BPD发病前得到治疗。
