Wada Akihiko
Department of Pharmacology, University of Miyazaki, Japan.
J Pharmacol Sci. 2009 May;110(1):14-28. doi: 10.1254/jphs.09r02cr. Epub 2009 May 8.
Mood disorders are not merely attributed to the functional defect of neurotransmission, but also are due to the structural impairment of neuroplasticity. Chronic stress decreases neurotrophin levels, precipitating or exacerbating depression; conversely, antidepressants increase expression of various neurotrophins (e.g., brain-derived neurotrophic factor and vascular endothelial growth factor), thereby blocking or reversing structural and functional pathologies via promoting neurogenesis. Since the worldwide approval of lithium therapy in 1970, lithium has been used for its anti-manic, antidepressant, and anti-suicidal effects, yet the therapeutic mechanisms at the cellular level remain not-fully defined. During the last five years, multiple lines of evidence have shown that the mood stabilization and neurogenesis by lithium are due to the lithium-induced inhibition of glycogen synthase kinase-3beta (GSK-3beta), allowing accumulation of beta-catenin and beta-catenin-dependent gene transcriptional events. Altered levels of GSK-3beta and beta-catenin are associated with various neuropsychiatric and neurodegenerative diseases, while various classical neuropsychiatric drugs inhibit GSK-3beta and up-regulate beta-catenin expression. In addition, evidence has emerged that insulin-like growth factor-I enhances antidepression, anti-anxiety, memory, neurogenesis, and angiogenesis; antidepressants up-regulate expression of insulin-like growth factor-I, while insulin-like growth factor-I up-regulates brain-derived neurotrophic factor expression and its receptor TrkB level, as well as brain-derived neurotrophic factor-induced synaptic protein levels. More importantly, physical exercise and healthy diet raise transport of peripheral circulating insulin-like growth factor I into the brain, reinforcing the expression of neurotrophins (e.g., brain-derived neurotrophic factor) and the strength of cell survival signalings (e.g., phosphoinositide 3-kinase / Akt / GSK-3beta pathway). This review will focus on the rapidly advancing new trends in the last five years about lithium, GSK-3beta/beta-catenin, and neurotrophin cascades.
情绪障碍不仅归因于神经传递的功能缺陷，还源于神经可塑性的结构损伤。慢性应激会降低神经营养因子水平，引发或加重抑郁；相反，抗抑郁药会增加各种神经营养因子（如脑源性神经营养因子和血管内皮生长因子）的表达，从而通过促进神经发生来阻断或逆转结构和功能病变。自1970年锂疗法在全球获批以来，锂因其抗躁狂、抗抑郁和抗自杀作用而被使用，但其在细胞水平的治疗机制仍未完全明确。在过去五年中，多条证据表明锂的情绪稳定和神经发生作用是由于锂诱导的糖原合酶激酶-3β（GSK-3β）抑制，使得β-连环蛋白积累以及β-连环蛋白依赖性基因转录事件发生。GSK-3β和β-连环蛋白水平的改变与多种神经精神疾病和神经退行性疾病相关，而各种经典神经精神药物会抑制GSK-3β并上调β-连环蛋白表达。此外，有证据表明胰岛素样生长因子-I可增强抗抑郁、抗焦虑、记忆、神经发生和血管生成作用；抗抑郁药会上调胰岛素样生长因子-I的表达，而胰岛素样生长因子-I会上调脑源性神经营养因子的表达及其受体TrkB水平，以及脑源性神经营养因子诱导的突触蛋白水平。更重要的是，体育锻炼和健康饮食会增加外周循环胰岛素样生长因子I向大脑的转运，增强神经营养因子（如脑源性神经营养因子）的表达以及细胞存活信号通路（如磷酸肌醇3激酶/Akt/GSK-3β通路）的强度。本综述将聚焦过去五年中关于锂、GSK-3β/β-连环蛋白和神经营养因子级联反应的快速发展的新趋势。
