Inhibition of Acid Sphingomyelinase by Antidepressants Counteracts Stress-Induced Activation of P38-Kinase in Major Depression
Inhibition of Acid Sphingomyelinase by Antidepressants Counteracts Stress-Induced Activation of P38-Kinase in Major Depression
复制标题
DOI：
10.1159/000442606
复制
发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
H. Grassmé;P. Jernigan;R. Hoehn;B. Wilker;Matthias Soddemann;M. Edwards;C. Müller;J. Kornhuber;E. Gulbins
中科院分区：
文献类型：
--
作者：
H. Grassmé;P. Jernigan;R. Hoehn;B. Wilker;Matthias Soddemann;M. Edwards;C. Müller;J. Kornhuber;E. Gulbins
背景/目的：重性抑郁障碍是一种常见的疾病，具有严重的发病率，包括自杀死亡的风险增加。重度抑郁症是用抗抑郁药治疗的。然而，抗抑郁药的分子靶点仍然不明确，需要进一步阐明。研究方法：小鼠用皮质酮诱导应激，阿米替林和p38激酶（p38 K）抑制剂SB 239063或这些药物的组合治疗。通过磷酸化特异性抗体免疫染色、BrdU标记的神经元增殖和采用一组行为测试的行为来确定海马神经元中p38 K的磷酸化。结果：皮质酮可诱导海马p38 K的磷酸化/活化。抗抑郁药逆转了皮质酮对野生型小鼠p38 K激活的影响，但对酸性鞘磷脂酶缺乏的动物没有影响。皮质酮还减少神经发生并引发抑郁样行为变化，这些作用可通过药理学抑制p38 K来预防。结论：应激诱导海马中的p38 K磷酸化/活化，从而减少神经发生并诱导抑郁样症状，抗抑郁药通过抑制酸性鞘磷脂酶/神经酰胺系统来预防这些事件。
Background/Aims: Major depressive disorder is a common disease with serious morbidity, including increased risk of death from suicide. Major depressive disorder is treated with antidepressants. However, the molecular targets of antidepressants remained ill-defined and require further elucidation. Methods: Mice were treated with corticosterone to induce stress, amitriptyline and the p38-kinase (p38K) inhibitor SB239063 or a combination of these drugs. Phosphorylation of p38K in hippocampal neurons was determined by immunostaining with a phospho-specific antibody, neuronal proliferation using BrdU-labelling and behaviour employing a set of behavioural tests. Results: Corticosterone induced phosphorylation/activation of p38K in the hippocampus in vivo. Antidepressants reversed the effect of corticosterone on p38K activation in wildtype mice, but had no effect in acid sphingomyelinase-deficient animals. Corticosterone also reduced neurogenesis and triggered depression-like behavioural changes, effects that were prevented by pharmacological inhibition of p38K. Conclusion: Stress induces p38K phosphorylation/activation in the hippocampus and thereby reduces neurogenesis and induces depression-like symptoms, events that are prevented by antidepressants via inhibition of the acid sphingomyelinase/ceramide system.