The acid sphingomyelinase/ceramide hypothesis of major depression

重度抑郁症的酸性鞘磷脂酶/神经酰胺假说

• 批准号: 173699717
• 负责人: Professor Dr. Erich Gulbins
• 金额: --
• 依托单位: Institut für Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/173699717?language=en
• 关键词: acid; sphingomyelinase; ceramide; hypothesis; major

Major depression is a severe and often life-threatening mood disorder. The molecular mechanisms resulting in major depression are, however, unknown. Previously, we found increased activity of the acid sphingomyelinase (ASM) in patients suffering from major depression, consistent with the finding of the functional inhibition of the ASM by antidepressant drugs. Data generated during the first funding period demonstrate that amitriptyline and fluoxetine inhibit the ASM in the hippocampus of stressed and resting mice, resulting in reduction of hippocampal ceramide, increased neurogenesis and behavioural effects, events that were all absent in ASM-deficient mice receiving these antidepressant drugs. 1) Amitriptyline and fluoxetine functionally inhibit ASM in concentrations used for antidepressant therapy. In mouse models, we will now determine whether or not the neurobiological and behavioural effects of antidepressive drugs and electroconvulsive stimulation are mediated by inhibition of the ASM; 2) in cell culture models, determine whether or not ASM is involved in processes relevant for synaptic transmission; 3) in human patients, study the role of ASM as a diagnostic marker.

重度抑郁症是一种严重且常常危及生命的情绪障碍。然而，导致重度抑郁症的分子机制尚不清楚。此前，我们发现重度抑郁症患者的酸性鞘磷脂酶（ASM）活性增加，这与抗抑郁药物对 ASM 功能性抑制的发现一致。第一个资助期间产生的数据表明，阿米替林和氟西汀抑制应激小鼠和静息小鼠海马中的 ASM，导致海马神经酰胺减少、神经发生和行为效应增加，而这些事件在接受这些抗抑郁药物的 ASM 缺陷小鼠中均不存在。 1) 阿米替林和氟西汀在抗抑郁治疗浓度下可有效抑制 ASM。在小鼠模型中，我们现在将确定抗抑郁药物和电惊厥刺激的神经生物学和行为效应是否是通过抑制 ASM 介导的； 2）在细胞培养模型中，确定ASM是否参与与突触传递相关的过程； 3）在人类患者中，研究ASM作为诊断标志物的作用。