Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
Nat Med. 2013 Jul;19(7):934-8. doi: 10.1038/nm.3214. Epub 2013 Jun 16.
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.
重度抑郁症是一种高发的严重情绪障碍，可采用抗抑郁药进行治疗。抗抑郁药的分子靶点需要明确。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可降低海马体中的 Asm 活性和神经酰胺浓度，增加神经元增殖、成熟和存活，并改善应激诱导的抑郁小鼠模型的行为。基因敲除 Asm 可消除这些作用。过表达 Asm 的小鼠、杂合酸性神经酰胺酶、用神经酰胺代谢抑制剂处理或直接向海马体注射 C16 神经酰胺的小鼠，其神经酰胺浓度更高，神经元增殖、成熟和存活的速度更慢，与对照组相比表现出抑郁样行为，即使在没有应激的情况下也是如此。通过抗抑郁药介导的 Asm 抑制来降低神经酰胺丰度可使这些作用正常化。因此，降低神经酰胺丰度可能是未来开发抗抑郁药的核心目标。
