GSK-3 Signaling: Targeting Actions of Mood Stablizing

糖原合成酶-3(GSK-3)直接被锂抑制，因此是一个有趣的候选新疗法的潜在靶点。GSK-3抑制剂作为新的治疗药物引起了极大的兴趣，选择性小分子化合物正在迅速开发，用于治疗包括糖尿病、阿尔茨海默病、中风和炎症在内的广泛疾病。有了令人信服的临床前证据，这些药物很可能会被用于双相情感障碍的试验。虽然GSK-3在1996年被确定为锂的体外靶点，但这种酶在成年哺乳动物大脑中的抑制程度在治疗上相关的浓度还没有确定，并阻碍了未来针对GSK-3抑制的双相情感障碍试验。在最近出版的《神经精神药理学》杂志上的一篇手稿中，我们利用亚细胞分离和实时聚合酶链式反应显示，在翻译后治疗血清浓度下的锂和丙戊酸可以调节大鼠大脑中的O-连环蛋白(GSK-3靶标和重要的转录因子)，这表明锂在体内显著抑制与治疗双相情感障碍相关的浓度的脑GSK-3。这一发现表明，两种结构不同的稳定情绪的药物对o-连环蛋白的作用相似，这表明该蛋白在治疗双相情感障碍方面可能具有重要意义。为了进一步阐明这种转录因子的重要性，我正在与约翰·霍普金斯大学的Charles Eberhart合作，研究转基因小鼠成年大脑中？o-catenin过度表达的行为和生化表现。目前正在进行的其他研究计划获得新的、特定的、GSK-3抑制剂在啮齿动物行为模型中的效果。 令人兴奋的是，这项工作可能有助于促进临床试验。然而，在GSK-3抑制剂的开发中，一个主要的问题是Wnt信号通路VOF，而GSK-3是其中一个重要的中间分子。因此，我们调查了一份手稿，并于最近发表在《药理学研究》上，该手稿描述了锂在易于形成Wnt途径肿瘤的小鼠模型中的作用；我们发现，锂治疗60天并不会增加肿瘤的数量。与我们自己的APC小鼠实验类似的研究对于确定新型GSK-3抑制剂在用于人类之前的安全性至关重要。 除了旨在了解GSK-3在双相情感障碍病理生理学和治疗中的作用的研究外，我们还在评估情绪稳定剂在一系列含有Cre-O半乳糖苷酶报告结构的小鼠中的效果(通过与华盛顿大学的Daniel Storm合作)。我们的团队已经证明锂和丙戊酸都可以增加CREB激活形式的水平；这些对Cre-O半乳糖苷酶报告小鼠的研究结果可能为这一观察提供更多证据，此外还提供了更大程度的区域和时间特异性。

Glycogen synthase kinase-3 (GSK-3), is directly inhibited by lithium, and as such is an interesting candidate as a potential target for novel therapeutics. 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 maladies including diabetes, Alzheimer's disease, stroke, and inflammation. With convincing preclinical evidence, it is likely that those medications developed will be utilized in bipolar disorder trials. Although GSK-3 was identified as in vitro target of lithium in 1996, the degree of inhibition of this enzyme in the adult mammalian brain at therapeutically relevant concentrations has not been established and was an impediment to future bipolar disorder trials directed at GSK-3 inhibition. In a manuscript currently in press in Neuropsychopharmacology, we showed, using subcellular fractionation and real-time PCR, that treatment with lithium and valproic acid at therapeutic serum concentrations postranslationally regulates ?O-catenin (a GSK-3 target and important transcription factor) in the rat brain, suggesting that lithium significantly inhibits brain GSK-3 in vivo at concentrations relevant for the treatment of bipolar disorder. The finding that two structurally dissimilar mood-stabilizing medications exert similar effects on ?O-catenin, suggests a possible importance of this protein in the treatment of bipolar disorder. To further address importance of this transcription factor, I am collaborating with Charles Eberhart (Johns Hopkins University) to investigate the behavioral and biochemical manifestations of over-expression of ?O-catenin in the adult brain of transgenic mice. Additional studies currently underway plan to access the effects of novel, specific, GSK-3 inhibitors in rodent behavioral models. It is exciting that this work may help facilitate clinical trials. However, a major concern in the development of GSK-3 inhibitors has been that the Wnt signaling pathway!Vof which GSK-3 is an important intermediary molecule!Vis implicated in many human cancers. We therefore investigated, and recently published in Pharmacological Research, a manuscript describing the effects of lithium in a murine model predisposed to the formation of tumors of the Wnt pathway!Xthe adenomatous polyposis coli (APC) mouse; we found that 60 days of lithium treatment did not increase the number of tumors. Similar studies to our own APC mouse experiments will be critical for establishing the safety of novel GSK-3 inhibitors prior to use in humans. In addition to the studies designed to understand the role of GSK-3 in bipolar disorder pathophysiology and treatment, we are also assessing the effects of mood stabilizer treatments in a line of mice containing a CRE-?O galactosidase reporter construct (through a collaboration with Daniel Storm, University of Washington). Both lithium and valproic acid have been shown by our group to increase the levels of the activated form of CREB; the results of these studies with CRE-?O galactosidase reporter mice may provide more evidence for this observation, in addition to providing a greater degree of regional and temporal specificity.