Gould Todd D, Zarate Carlos A, Manji Husseini K
Laboratory of Molecular Pathophysiology, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA.
J Clin Psychiatry. 2004 Jan;65(1):10-21.
The enzyme glycogen synthase kinase-3 (GSK-3) is a direct target of lithium. While originally recognized as an important molecule in a limited number of cellular processes, with unclear significance for the treatment of bipolar disorder, recent evidence suggests it has critically important cellular functions in the adult brain. GSK-3 has an essential role in a number of signaling pathways and regulates the function of a diverse number of proteins, notably transcription factors and cytoskeletal elements. The most important functions of the enzyme in regard to bipolar disorder may be critical effects on cellular resilience and neuronal plasticity. There is tremendous interest in GSK-3 inhibitors as novel therapeutic agents, and selective, small-molecule compounds are rapidly being developed for a broad range of other maladies including diabetes, Alzheimer's disease, stroke, and inflammatory conditions. In this perspectives article, we provide an overview of the molecular targets of lithium, focusing on GSK-3-regulated signaling pathways and the important functions of GSK-3 that may have relevance for the treatment of bipolar disorder. We conclude with a discussion of the GSK-3 inhibitors furthest in development and the clinical trials that may emerge.
糖原合酶激酶-3（GSK-3）是锂的直接作用靶点。虽然最初它被认为是少数细胞过程中的重要分子，对双相情感障碍治疗的意义尚不明确，但最近的证据表明它在成人大脑中具有至关重要的细胞功能。GSK-3在多种信号通路中发挥着重要作用，并调节多种蛋白质的功能，尤其是转录因子和细胞骨架成分。就双相情感障碍而言，该酶最重要的功能可能是对细胞恢复力和神经元可塑性产生关键影响。人们对GSK-3抑制剂作为新型治疗药物有着浓厚兴趣，并且正在迅速开发选择性小分子化合物用于治疗包括糖尿病、阿尔茨海默病、中风和炎症性疾病在内的广泛其他疾病。在这篇观点文章中，我们概述了锂的分子靶点，重点关注GSK-3调节的信号通路以及可能与双相情感障碍治疗相关的GSK-3的重要功能。我们最后讨论了研发进展最远的GSK-3抑制剂以及可能出现的临床试验。
