Leicester School of Pharmacy, De Montfort University, Leicester, UK.
J Psychopharmacol. 2020 Jul;34(7):716-725. doi: 10.1177/0269881120915412. Epub 2020 May 14.
Major depression is a common mood disorder and the central sphingolipid system has been identified as a possible drug target of this condition. Here we investigated the action of antidepressant drugs on sphingolipid levels in rat brain regions, plasma and in cultured mouse macrophages.
Two antidepressant drugs were tested: the serotonin reuptake inhibitor paroxetine and the noradrenaline reuptake inhibitor desipramine, either following acute or chronic treatments. Content of sphingosine and ceramide were analysed using LC-MS or HPLC-UV, respectively. This was from samples of brain, plasma and cultured mouse macrophages. Antidepressant-induced effects on mRNA expression for two key genes of the sphingolipid pathway, and , were also measured by using quantitative real-time PCR.
Chronic but not acute administration of paroxetine or desipramine reduced sphingosine levels in the prefrontal cortex and hippocampus (only paroxetine) but not in the striatum. Ceramide levels were also measured in the hippocampus following chronic paroxetine and likewise to sphingosine this treatment reduced its levels. The corresponding collected plasma samples from chronically treated animals did not show any decrease of sphingosine compared to the corresponding controls. Both drugs failed to reduce sphingosine levels from cultured mouse macrophages. The drug-induced decrease of sphingolipids coincided with reduced mRNA expression of two enzymes of the central sphingolipid pathway, i.e. acid sphingomyelinase () and acid ceramidase ().
This study supports the involvement of brain sphingolipids in the mechanism of action by antidepressant drugs and for the first time highlights their differential effects on brain versus plasma levels.
重度抑郁症是一种常见的情绪障碍，中央神经鞘脂系统已被确定为这种疾病的可能药物靶点。在这里，我们研究了抗抑郁药对大鼠脑区、血浆和培养的小鼠巨噬细胞中神经鞘脂水平的作用。
测试了两种抗抑郁药：选择性 5-羟色胺再摄取抑制剂帕罗西汀和去甲肾上腺素再摄取抑制剂去甲替林，分别进行急性或慢性治疗。使用 LC-MS 或 HPLC-UV 分别分析神经鞘氨醇和神经酰胺的含量。这些样本来自大脑、血浆和培养的小鼠巨噬细胞。还通过定量实时 PCR 测量抗抑郁药对神经鞘脂途径的两个关键基因 和 的 mRNA 表达的诱导作用。
帕罗西汀或去甲替林的慢性而非急性给药可降低前额叶皮层和海马体（仅帕罗西汀）中的神经鞘氨醇水平，但不能降低纹状体中的神经鞘氨醇水平。同样，在慢性帕罗西汀处理后还测量了海马体中的神经酰胺水平，与神经鞘氨醇一样，这种治疗降低了其水平。与相应的对照相比，来自慢性治疗动物的相应收集的血浆样本中没有显示出神经鞘氨醇的任何降低。两种药物均未能降低培养的小鼠巨噬细胞中的神经鞘氨醇水平。药物诱导的神经鞘脂降低与中央神经鞘脂途径的两种酶，即酸性鞘磷脂酶（）和酸性神经酰胺酶（）的 mRNA 表达减少相吻合。
本研究支持脑神经鞘脂参与抗抑郁药的作用机制，并且首次强调了它们对大脑与血浆水平的不同影响。
