Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs
Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs
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DOI：
10.1038/nm.3214
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发表时间：
2013-07-01
期刊：
影响因子：
82.9
通讯作者：
Kornhuber, Johannes
中科院分区：
文献类型：
--
作者：
Gulbins, Erich;Palmada, Monica;Kornhuber, Johannes
重度抑郁症是一种非常普遍的严重情绪障碍，可以用抗抑郁药治疗。抗抑郁药的分子靶点需要定义。我们研究了酸性鞘磷脂酶（Asm）-神经酰胺系统作为抗抑郁药靶点的作用。治疗浓度的抗抑郁药阿米替林和氟西汀降低了海马中Asm活性和神经酰胺浓度，增加了神经元增殖、成熟和存活，并改善了应激诱导抑郁症小鼠模型的行为。遗传性Asm缺乏消除了这些影响。过表达Asm的小鼠，酸性神经酰胺酶的杂合子，用神经酰胺代谢阻断剂治疗或在海马直接注射C16神经酰胺，与对照组相比，神经酰胺浓度较高，神经元增殖、成熟和存活率较低，即使在没有压力的情况下也表现出抑郁样行为。通过抗抑郁药介导的Asm抑制实现的神经酰胺丰度的减少使这些效应正常化。因此，降低神经酰胺丰度可能是未来开发抗抑郁药的中心目标。
Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants.