Fingolimod modulates microglial activation to augment markers of remyelination.
Fingolimod modulates microglial activation to augment markers of remyelination.
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DOI：
10.1186/1742-2094-8-76
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发表时间：
2011-07-05
影响因子：
9.3
通讯作者：
Baker D
中科院分区：
文献类型：
--
作者：
Jackson SJ;Giovannoni G;Baker D
多发性硬化症中的小胶质细胞激活被认为是疾病期间长期神经退行性变的原因。已显示芬戈莫德通过调节自身反应性T细胞从淋巴器官的排出来影响疾病的复发缓解期。此外，它是大脑渗透剂，并已被证明对神经系统细胞产生多种影响。在这项研究中，在大鼠端脑再聚集球体细胞培养系统中检查了芬戈莫德和其他鞘氨醇-1-磷酸受体活性分子在溶血磷脂酰胆碱诱导的脱髓鞘后的影响。由于缺乏免疫系统组分，因此可以阐明芬戈莫德在器官型情况下对CNS细胞类型的直接影响。脱髓鞘后，芬戈莫德显著增加髓鞘形成期髓鞘碱性蛋白的表达。这种增加与神经丝水平的变化无关，表明新生髓鞘蛋白表达与轴突分支无关。使用共聚焦和电子显微镜在形态学上证实了髓鞘包裹。当芬戈莫德存在时，髓鞘再生增加与脱髓鞘过程中小胶质细胞铁蛋白、肿瘤坏死因子α和白细胞介素1的下调相关。此外，在芬戈莫德存在下，脱髓鞘过程中一氧化氮代谢产物和凋亡效应物半胱天冬酶3和半胱天冬酶7减少。鞘氨醇-1-磷酸受体1和5激动剂BAF 312也增加了髓鞘碱性蛋白水平，而鞘氨醇-1-磷酸受体1激动剂AUY 954未能复制这种对髓鞘再生的影响。所呈现的结果表明，S1 P受体的调节可以改善与小胶质细胞活化相关的病理效应物，导致随后的髓鞘再生的蛋白质和形态学标志物的增加。此外，鞘氨醇-1-磷酸受体5参与促进体外髓鞘再生。这些知识可能对多发性硬化症中慢性小胶质细胞炎症的治疗有益。
Microglial activation in multiple sclerosis has been postulated to contribute to long-term neurodegeneration during disease. Fingolimod has been shown to impact on the relapsing remitting phase of disease by modulating autoreactive T-cell egress from lymph organs. In addition, it is brain penetrant and has been shown to exert multiple effects on nervous system cells. In this study, the impact of fingolimod and other sphingosine-1-phosphate receptor active molecules following lysophosphotidyl choline-induced demyelination was examined in the rat telencephalon reaggregate, spheroid cell culture system. The lack of immune system components allowed elucidation of the direct effects of fingolimod on CNS cell types in an organotypic situation. Following demyelination, fingolimod significantly augmented expression of myelin basic protein in the remyelination phase. This increase was not associated with changes in neurofilament levels, indicating de novo myelin protein expression not associated with axonal branching. Myelin wrapping was confirmed morphologically using confocal and electron microscopy. Increased remyelination was associated with down-regulation of microglial ferritin, tumor necrosis factor alpha and interleukin 1 during demyelination when fingolimod was present. In addition, nitric oxide metabolites and apoptotic effectors caspase 3 and caspase 7 were reduced during demyelination in the presence of fingolimod. The sphingosine-1-phosphate receptor 1 and 5 agonist BAF312 also increased myelin basic protein levels, whereas the sphingosine-1-phosphate receptor 1 agonist AUY954 failed to replicate this effect on remyelination. The results presented indicate that modulation of S1P receptors can ameliorate pathological effectors associated with microglial activation leading to a subsequent increase in protein and morphological markers of remyelination. In addition, sphingosine-1-phosphate receptor 5 is implicated in promoting remyelination in vitro. This knowledge may be of benefit for treatment of chronic microglial inflammation in multiple sclerosis.
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影响因子：
6.2
作者：
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通讯作者：
Cuzner, ML
影响因子：
3.4
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