Testing whether the enzyme GSK-3 is a therapeutically relevant target of lithium

情绪稳定剂锂能抑制一组特定的酶，包括糖原合成酶-3(GSK-3)。然而，目前尚不清楚锂离子抑制GSK-3是否与其抗躁狂和抗抑郁效果有关。我们正在利用生化、细胞、组织化学、基因组和行为验证方法来研究GSK-3的抑制是否是锂的临床效应机制的一个组成部分。 我们正在利用啮齿动物行为模型和两种不同但互补的方法(药物抑制和转基因基因表达)，试图进一步验证GSK-3作为石膏治疗效果的可能介体。具体地说，GSK-3的主要靶点之一是转录因子β-连环蛋白。我们已经证明，在一个临床相关的范例中，给大鼠服用锂会导致β-连环素水平的增加。我们正在研究β-连环素在小鼠大脑中过度表达和低表达的影响，以及增加β-连环素的药理机制。使用这两种方法，我们发现啮齿动物既表现出抗抑郁药样行为，也表现出抗躁狂样行为。总而言之，这些数据支持锂可能发挥其抗抑郁作用和 GSK-3抑制剂通过抑制GSK-3发挥抗躁狂作用，新的小分子GSK-3抑制剂可能代表了一类真正用于治疗双相情感障碍和抑郁症的新型药物。验证锂的治疗靶点将需要 使用新型抑制剂的临床试验，其开发正在进行中。

The mood stabilizer lithium inhibits a select group of enzymes, including glycogen synthase kinase-3 (GSK-3). However, it is unclear if lithiums inhibition of GSK-3 is relevant for its antimanic and antidepressant effectiveness. We are utilizing biochemical, cellular, histochemical, genomic, and behavioral validation approaches to investigate whether the inhibition of GSK-3 is an integral part of the mechanism of lithiums clinical effects. We are utilizing rodent behavioral models and two distinct but complementary approaches (pharmacologic inhibition and transgenic gene expression) in an attempt to further validate GSK-3 as a possible mediator of lithiums therapeutic effects. Specifically, one of the primary targets of GSK-3 is the transcription factor beta-catenin. We have shown that lithium administration to rats, in a clinically relevant paradigm, results in an increase in beta- catenin levels. We are studying the effects of both over-expression and under-expression of beta-catenin in the mouse brain as well as pharmacological mechanisms to increase beta-catenin. Using both approaches, we have found the rodents exhibit both antidepressant-like and antimanic-like behavior. Combined, these data support the hypothesis that lithium may exert its antidepressant and antimanic effects through inhibition of GSK-3, and that novel small-molecule GSK-3 inhibitors may represent a truly novel class of medications useful for the treatment of bipolar disorder and depression. Validation of lithiums therapeutic target will require clinical trials with novel inhibitors, the development of which is in progress.