Local delivery of FTY720 in PCL membrane improves SCI functional recovery by reducing reactive astrogliosis.
Local delivery of FTY720 in PCL membrane improves SCI functional recovery by reducing reactive astrogliosis.
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DOI：
10.1016/j.biomaterials.2015.04.060
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发表时间：
2015-09
期刊：
影响因子：
14
通讯作者：
Junjuan Wang;Jiaqiu Wang;Ping Lu;Youzhi Cai;Yafei Wang;Lan Hong;Hao Ren;B. Heng;Hua Liu-Hua-Li
中科院分区：
文献类型：
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作者：
Junjuan Wang;Jiaqiu Wang;Ping Lu;Youzhi Cai;Yafei Wang;Lan Hong;Hao Ren;B. Heng;Hua Liu-Hua-Li
FTY720最近已被批准作为治疗复发性多发性硬化症的口服药物，并通过作为针对T细胞的鞘氨醇-1-磷酸(S1P)受体亚型(S1P1)的免疫抑制剂发挥其治疗作用。最近的研究表明，这种药物在全身给药后对动物模型的脊髓损伤(SCI)有积极的疗效，尽管有显著的副作用。我们在此假设，FTY720的局部注射可以通过减少病理性星形胶质细胞增生来促进脊髓损伤的恢复。采用免疫荧光、组织学、核磁共振和行为分析等方法，在体外研究了FTY720的作用机制。体外研究表明，FTY720可以减少S1P激活的星形胶质细胞迁移和增殖。FTY720可延长S1P1的内化，并对S1P1产生拮抗作用。在脊髓损伤动物模型的活体研究中，局部应用FTY720结合聚己内酯(PCL)膜可显著降低S1P1的表达，减少胶质瘢痕形成。此外，FTY720治疗组的空化体积和神经元丢失较少，显著促进了运动功能的恢复。这些结果表明，局部应用FTY720可以通过靶向星形胶质细胞的S1P1受体促进脊髓损伤的恢复，为脊髓损伤的治疗提供了新的治疗策略。
FTY720 has recently been approved as an oral drug for treating relapsing forms of multiple sclerosis, and exerts its therapeutic effect by acting as an immunological inhibitor targeting the sphingosine-1-phosphate (S1P) receptor subtype (S1P1) of T cells. Recently studies demonstrated positive efficacy of this drug on spinal cord injury (SCI) in animal models after systemic administration, albeit with significant adverse side effects. We hereby hypothesize that localized delivery of FTY720 can promote SCI recovery by reducing pathological astrogliosis. The mechanistic functions of FTY720 were investigatedin vitroandin vivoutilizing immunofluorescence, histology, MRI and behavioral analysis. Thein vitrostudy showed that FTY720 can reduce astrocyte migration and proliferation activated by S1P. FTY720 can prolong internalization of S1P1 and exert antagonistic effects on S1P1.In vivostudy of SCI animal models demonstrated that local delivery of FTY720 with polycaprolactone (PCL) membrane significantly decreased S1P1 expression and glial scarring compared with the control group. Furthermore, FTY720-treated groups exhibited less cavitation volume and neuron loss, which significantly improved recovery of motor function. These findings demonstrated that localized delivery of FTY720 can promote SCI recovery by targeting the S1P1 receptor of astrocytes, provide a new therapeutic strategy for SCI treatment.