Regulation of Neuronal Stem Cell Proliferation in the Hippocampus by Endothelial Ceramide
Regulation of Neuronal Stem Cell Proliferation in the Hippocampus by Endothelial Ceramide
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DOI：
10.1159/000447789
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发表时间：
2016-01-01
影响因子：
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通讯作者：
Gulbins, Erich
中科院分区：
文献类型：
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作者：
Gulbins, Anne;Grassme, Heike;Gulbins, Erich
背景/目的：重性抑郁症是西方国家最常见的疾病之一。该疾病主要由其精神症状来定义。然而，这种疾病也有许多中枢神经系统以外的症状，特别是心血管症状。近年来的研究表明，酸性鞘磷脂酶/神经酰胺系统在抑郁症的发生发展中起着重要作用，并可作为抗抑郁药物的作用靶点。研究方法：在此，我们研究了（i）在糖皮质酮介导的应激后，神经酰胺是否在海马神经发生区的内皮细胞中积累，（ii）神经酰胺是否被释放到海马的细胞外空间，以及（iii）细胞外神经酰胺是否抑制神经元增殖。神经酰胺测定内皮细胞培养上清液或细胞外海马提取物中的激酶测定。通过用γ 3标记的抗神经酰胺抗体和FITC-异凝集素B4染色的脑切片的共聚焦显微镜分析海马中的内皮神经酰胺。通过将嗜铬细胞瘤神经元细胞与培养上清液和细胞外海马提取物孵育来测量神经元增殖。结果：用糖皮质酮处理培养的内皮细胞可诱导神经酰胺释放到上清液中。同样，用糖皮质酮治疗小鼠会触发神经酰胺释放到海马的细胞外空间。与抗抑郁药阿米替林同时治疗可抑制神经酰胺的释放，阿米替林也可抑制酸性鞘磷脂酶的活性。采用共聚焦显微镜的研究表明，神经酰胺的形成和积累只在内皮细胞中的海马应激小鼠，这一过程再次阻止共同应用阿米替林。神经酰胺释放到培养上清液或海马细胞外间隙减少体外神经元的增殖。结论：这些数据表明了一种新的模型的发病机制的严重抑郁症，即释放神经酰胺富集微泡从内皮细胞的负面影响海马神经元的增殖，但也可能诱发心血管疾病和其他全身症状的严重抑郁症患者。(C)2016作者（s）由S. Karger AG，巴塞尔
Background/Aims: Major depressive disorder is one of the most common diseases in western countries. The disease is mainly defined by its psychiatric symptoms. However, the disease has also many symptoms outside the central nervous system, in particular cardiovascular symptoms. Recent studies demonstrated that the acid sphingomyelinase/ceramide system plays an important role in the development of major depressive disorder and functions as a target of antidepressants. Methods: Here, we investigated (i) whether ceramide accumulates in endothelial cells in the neurogenetic zone of the hippocampus after glucocorticosteronemediated stress, (ii) whether ceramide is released intothe extracell u lar space of the hi ppocampus and (iii) whether extracellular ceramide inhibits neuronal proliferation. Ceramide was determined in endothelial cell culture supernatants or extracellular hi ppocampus extracts by a kinase assay. Endothelial ceramide in the hippocampus was analyzed by confocal microscopy of brain sections stained with [y3-labelled anti-ceramide antibodies and FITC-Isolectin B4. Neuronal proliferation was measured by incubation of pheochromocytoma neuronal cells with culture supernatants and extracellular hippocampus extracts. Results: Treatment of cultured endothelial cells with glucocorticosterone induces a release of ceramide into the supernatant. Likewise, treatment of mice with glucocorticosterone triggers a release of ceramide into the extracellular space of the hippocampus. The release of ceramide is inhibited by concomitant treatment with the antidepressant amitriptyline, which also inhibits the activity of the acid sphingomyelinase. Studies employing confocal microscopy revealed that ceramide is formed and accumulates exclusively in endothelial cells in the hippocampus of stressed mice, a process that was again prevented by co-application of amitriptyline. Ceramide released in the culture supernatant or into the extracellular space of the hippocampus reduced proliferation of neurons in vitro. Conclusion: The data suggest a novel model for the pathogenesis of major depressive disorder, i.e. the release of ceramide-enriched microvesicles from endothelial cells that negatively affect neuronal proliferation in the hippocampus, but may also induce cardiovascular disease and other systemic symptoms of patients with major depressive disorder. (C) 2016 The Author(s) Published by S. Karger AG, Basel