Centre for Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
J Neuroinflammation. 2011 Jul 5;8:76. doi: 10.1186/1742-2094-8-76.
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.
多发性硬化症中的小胶质细胞激活被认为是导致疾病过程中神经退行性变的长期原因。 fingolimod 通过调节自身反应性 T 细胞从淋巴器官中流出，已显示出对疾病的复发缓解期有影响。此外，它具有脑穿透性，并已显示出对神经系统细胞的多种作用。
在这项研究中，在大鼠端脑聚集物，球体细胞培养系统中，研究了 fingolimod 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作用。由于缺乏免疫系统成分，因此可以在器官样条件下阐明 fingolimod 对中枢神经系统细胞类型的直接作用。
脱髓鞘后，fingolimod 在再髓鞘阶段显著增加了髓鞘碱性蛋白的表达。这种增加与神经丝水平的变化无关，表明与轴突分支无关的新髓鞘蛋白表达。使用共聚焦和电子显微镜学从形态学上证实了髓鞘包裹。在存在 fingolimod 的情况下，脱髓鞘时，小胶质细胞铁蛋白，肿瘤坏死因子α和白细胞介素 1 的表达下调与再髓鞘化有关。此外，在存在 fingolimod 的情况下，脱髓鞘过程中一氧化氮代谢产物和凋亡效应子 caspase 3 和 caspase 7 减少。鞘氨醇-1-磷酸受体 1 和 5 激动剂 BAF312 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 AUY954 未能复制再髓鞘化的这种作用。
提出的结果表明，调节 S1P 受体可以改善与小胶质细胞激活相关的病理性效应物，从而随后增加蛋白质和再髓鞘化的形态学标志物。此外，鞘氨醇-1-磷酸受体 5 参与促进体外再髓鞘化。这一知识可能有益于多发性硬化症中慢性小胶质细胞炎症的治疗。
