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

测试酶 GSK-3 是否是锂的治疗相关靶点

• 批准号: 7594572
• 负责人: HUSSEINI K MANJI
• 金额: $ 89.13万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7594572
• 关键词: Antidepressive Agents; Antimanic Agents; Behavior; Behavioral Model; Biochemical; Bipolar Disorder; Brain; Class; Clinical Trials; Data; Development; Effectiveness; Enzymes; Exhibits; Functional disorder; Gene Expression; Glycogen Synthase Kinase 3; Goals; Lithium; Mediator of activation protein; Mental Depression; Mood Disorders; Mood stabilizers; Mus; Pharmaceutical Preparations; Rattus; Rodent; Role; Synaptic Receptors; Synaptic plasticity; Testing; Therapeutic Effect; Transgenic Organisms; Validation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; behavioral genomics; beta catenin; clinical effect; clinically relevant; inhibitor/antagonist; novel; small molecule; therapeutic target; transcription factor

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.

心境稳定剂锂抑制一组选定的酶，包括糖原合成酶激酶3 （GSK-3）。然而，目前尚不清楚锂对GSK-3的抑制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的抑制是否是锂临床效应机制的一个组成部分。