GSK-3 Signaling: Targeting Actions of Mood Stablizing

糖原合成酶激酶3 （GSK-3）被锂直接抑制，因此作为新疗法的潜在靶点是一个有趣的候选者。GSK-3抑制剂作为一种新型的治疗药物引起了人们极大的兴趣，选择性的小分子化合物正在迅速地被开发用于广泛的疾病，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的试验。虽然GSK-3在1996年被确定为锂的体外靶点，但在治疗相关浓度下，该酶在成年哺乳动物大脑中的抑制程度尚未确定，这是未来针对GSK-3抑制的双相障碍试验的障碍。在《神经精神药理学》杂志上发表的一篇论文中，我们利用亚细胞分离和实时聚合酶链式反应（real-time PCR）表明，锂和丙戊酸治疗后的治疗血清浓度可调节？大鼠脑中的O-catenin （GSK-3靶点和重要转录因子），表明锂在体内显著抑制脑GSK-3，其浓度与双相情感障碍的治疗相关。研究发现，两种结构不同的情绪稳定药物对人体的影响相似。o -连环蛋白，表明这种蛋白在治疗双相情感障碍中可能具有重要意义。为了进一步阐明这一转录因子的重要性，我正在与Charles Eberhart（约翰霍普金斯大学）合作研究？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获得新的，特异性的GSK-3抑制剂的效果。

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.