富马酸对杯状细胞溶解素诱导的小鼠中枢神经系统脱髓鞘和髓鞘再生的影响。

BACKGROUND

Fumaric acid esters (FAE) are a group of compounds which are currently under investigation as an oral treatment for relapsing-remitting multiple sclerosis. One of the suggested modes of action is the potential of FAE to exert a neuroprotective effect.

METHODOLOGY/PRINCIPAL FINDINGS: We have investigated the impact of monomethylfumarate (MMF) and dimethylfumaric acid (DMF) on de- and remyelination using the toxic cuprizone model where the blood-brain-barrier remains intact and only scattered T-cells and peripheral macrophages are found in the central nervous system (CNS), thus excluding the influence of immunomodulatory effects on peripheral immune cells. FAE showed marginally accelerated remyelination in the corpus callosum compared to controls. However, we found no differences for demyelination and glial reactions in vivo and no cytoprotective effect on oligodendroglial cells in vitro. In contrast, DMF had a significant inhibitory effect on lipopolysaccharide (LPS) induced nitric oxide burst in microglia and induced apoptosis in peripheral blood mononuclear cells (PBMC).

CONCLUSIONS

These results contribute to the understanding of the mechanism of action of fumaric acids. Our data suggest that fumarates have no or only little direct protective effects on oligodendrocytes in this toxic model and may act rather indirectly via the modulation of immune cells.

背景

富马酸酯（FAE）是一组化合物，目前正在作为复发性缓解型多发性硬化症的口服治疗方法进行研究。其作用机制之一是 FAE 具有神经保护作用的潜力。

方法/主要发现：我们使用完整血脑屏障的神经毒素 cuprizone 模型研究了单甲基富马酸（MMF）和二甲基富马酸（DMF）对脱髓鞘和髓鞘再生的影响，在该模型中仅在中枢神经系统（CNS）中发现散在的 T 细胞和外周巨噬细胞，从而排除了外周免疫细胞的免疫调节作用的影响。与对照组相比，FAE 在胼胝体中显示出轻微加速的髓鞘再生。然而，我们在体内未发现脱髓鞘和神经胶质反应的差异，也未发现对体外少突胶质细胞的细胞保护作用。相比之下，DMF 对脂多糖（LPS）诱导的小胶质细胞中一氧化氮爆发具有显著的抑制作用，并诱导外周血单核细胞（PBMC）凋亡。