GSK-3 Signaling: Targeting Actions of Mood Stablizing

糖原合酶激酶-3（GSK-3）直接被锂抑制，因此是作为新型治疗剂的潜在靶点的令人感兴趣的候选者。人们对GSK-3抑制剂作为新型治疗剂产生了极大的兴趣，并且正在迅速开发用于广泛疾病的选择性小分子化合物，包括糖尿病、阿尔茨海默病、中风和炎症。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试验。尽管GSK-3在1996年被确定为锂的体外靶点，但在治疗相关浓度下成年哺乳动物大脑中这种酶的抑制程度尚未确定，这是未来针对GSK-3抑制的双相情感障碍试验的障碍。在一份手稿，目前在出版的神经精神药理学，我们表明，使用亚细胞分级和实时PCR，治疗锂和丙戊酸在治疗血清浓度translationally调节？0-连环蛋白（GSK-3靶标和重要的转录因子），表明锂在与治疗双相情感障碍相关的浓度下显著抑制体内脑GSK-3。发现两种结构不同的情绪稳定药物产生相似的效果？O-catenin，表明这种蛋白质在治疗双相情感障碍中的可能重要性。为了进一步解决这个转录因子的重要性，我与查尔斯Eberhart（约翰霍普金斯大学）合作，调查行为和生化表现的过度表达？转基因小鼠成年脑中的O-连环蛋白。目前正在进行的其他研究计划在啮齿动物行为模型中评估新型特异性GSK-3抑制剂的作用。 令人兴奋的是，这项工作可能有助于促进临床试验。然而，GSK-3抑制剂开发中的一个主要问题是Wnt信号通路！其中GSK-3是一个重要的中间分子！维斯与许多人类癌症有关。因此，我们研究，并最近发表在药理学研究，一份手稿描述了锂在小鼠模型中的作用，该模型易形成Wnt通路的肿瘤！在腺瘤性结肠息肉病（APC）小鼠中，我们发现60天的锂治疗没有增加肿瘤的数量。与我们自己的APC小鼠实验类似的研究对于在用于人类之前确定新型GSK-3抑制剂的安全性至关重要。 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，我们还评估了情绪稳定剂治疗在一系列含有CRE-？O半乳糖苷酶报告基因构建体（通过与华盛顿大学的丹尼尔斯托姆合作）。锂和丙戊酸已被证明由我们的小组，以增加CREB的活化形式的水平，这些研究的结果与CRE-？O半乳糖苷酶报告小鼠除了提供更大程度的区域和时间特异性外，还可以为这一观察提供更多的证据。

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.