Tahmasebi Fatemeh, Pasbakhsh Parichehr, Mortezaee Keywan, Madadi Soheila, Barati Shirin, Kashani Iraj Ragerdi
Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
J Cell Biochem. 2019 Jun;120(6):10576-10586. doi: 10.1002/jcb.28344. Epub 2019 Jan 10.
Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system (CNS). Despite introducing multiple immunomodulatory approaches for MS, there are still major concerns about possible ways for improving remyelination in this disease. Microglia exert essential roles in regulation of myelination processes, and interaction between colony-stimulating factor 1 (CSF1) with its receptor CSF1R is considered as a key regulator of microglial differentiation and survival. The aim of this study was to investigate possible roles for a CSF1R inhibitor PLX3397 in recovery of central myelination processes. Chronic demyelination was induced in mice by addition of 0.2% cuprizone to the chow for 12 weeks. Next, animals were undergoing a diet containing 290 mg/kg PLX3397 to induce microglial ablation. The PLX3397 treatment caused a significant decrease in the rate of expression for the CSF1/CSF1R axis, and a reduction in the protein expressions for the microglial marker Iba-1 and for the oligodendrocyte marker Olig-2. Findings from Luxol fast blue (LFB) staining and transmission electron microscopy (TEM) showed an increase in the rate of myelination for the mice receiving PLX3397. The rate of destruction in the nerve fibers and the extent of the gaps formed between layers of myelin sheaths was also reduced after the treatment with PLX3397. In addition, animals experienced an improvement in recovery of motor deficit after receiving PLX3397 (for all P < 0.05). It could be concluded that PLX3397 could retain myelination in the MS model possibly through regulation of the myelin environment.
多发性硬化症（MS）是一种影响中枢神经系统（CNS）的慢性炎症性疾病。尽管已针对MS引入了多种免疫调节方法，但对于改善该疾病中髓鞘再生的可能途径仍存在重大担忧。小胶质细胞在髓鞘形成过程的调节中发挥着重要作用，集落刺激因子1（CSF1）与其受体CSF1R之间的相互作用被认为是小胶质细胞分化和存活的关键调节因子。本研究的目的是探讨CSF1R抑制剂PLX3397在中枢髓鞘形成过程恢复中的可能作用。通过在饲料中添加0.2%的铜螯合剂12周，在小鼠中诱导慢性脱髓鞘。接下来，让动物食用含有290mg/kg PLX3397的饮食以诱导小胶质细胞消融。PLX3397治疗导致CSF1/CSF1R轴的表达率显著降低，小胶质细胞标志物Iba-1和少突胶质细胞标志物Olig-2的蛋白表达减少。Luxol固蓝（LFB）染色和透射电子显微镜（TEM）的结果显示，接受PLX3397的小鼠的髓鞘形成率增加。在用PLX3397治疗后，神经纤维的破坏率以及髓鞘层之间形成的间隙程度也降低了。此外，动物在接受PLX3397后运动功能障碍的恢复情况有所改善（所有P<0.05）。可以得出结论，PLX3397可能通过调节髓鞘环境在MS模型中保留髓鞘形成。
