FTY720 Improves Functional Recovery after Spinal Cord Injury by Primarily Nonimmunomodulatory Mechanisms
FTY720 Improves Functional Recovery after Spinal Cord Injury by Primarily Nonimmunomodulatory Mechanisms
复制标题
DOI：
10.1016/j.ajpath.2011.12.012
复制
发表时间：
2012-04-01
影响因子：
6
通讯作者：
Sakata, Yoichi
中科院分区：
文献类型：
--
作者：
Norimatsu, Yusuke;Ohmori, Tsukasa;Sakata, Yoichi
脊髓损伤(SCI)是一种致残损伤，可导致有限的功能恢复。我们先前已经发现，脊髓挫伤后，溶血磷脂介质--1-磷酸鞘氨醇(SIP)含量增加。为了将S1P受体调控应用于脊髓损伤的治疗，我们观察了S1P受体激动剂FTY720对小鼠脊髓损伤后运动功能恢复的治疗作用。在脊髓挫伤后不久口服FTY720显著地促进了运动功能的恢复，这是通过Basso小鼠评分和旋转棒性能测试结果来评估的。FTY720可诱导脊髓损伤后淋巴细胞减少，减少T细胞在脊髓中的浸润，但不影响中性粒细胞的早期浸润和小胶质细胞的激活。此外，FTY720不能降低脊髓损伤后血浆和脊髓中炎性细胞因子的水平和mRNA的表达。FTY720可降低损伤脊髓的血管通透性和星形胶质细胞积聚。FTY720的治疗作用并不完全依赖于免疫调节，FTY720也改善了严重联合免疫缺陷小鼠的脊髓损伤后的运动功能。最后，S1P(1)受体激动剂SEW2871部分模拟了FTY720的治疗效果。我们的数据强调了FTY720的免疫非依赖性功能在降低脊髓损伤后血管通透性和星形胶质细胞增生以及促进运动功能恢复方面的重要性。(Am J Pathol2012,180：1625-1635；doi：10.1016/j.ajpath.2011.12.012)
Spinal cord injury (SCI) is an incapacitating injury that can result in limited functional recovery. We have previously shown increases in the lysophospholipid mediator, sphingosine-1-phosphate (SIP), in the spinal cord after contusion injury. To apply S1P receptor modulation to the treatment of SCI, we examined the therapeutic effects of FTY720, an S1P receptor agonist, on locomotor recovery after SCI in mice. Oral administration of FTY720 shortly after contusion SCI significantly improved motor function recovery, as assessed by both Basso Mouse Scale scores and Rotarod Performance test results. FTY720 induced lymphopenia and reduced T-cell infiltration in the spinal cord after SCI but did not affect the early infiltration of neutrophils and the activation of microglia. In addition, plasma levels and mRNA expression of inflammatory cytokines in the spinal cord after SCI were not attenuated by FTY720. Vascular permeability and astrocyte accumulation were both decreased by FTY720 in the injured spinal cord. The therapeutic effects of FTY720 were not solely dependent on immune modulation, as confirmed by the demonstration that FTY720 also ameliorated motor function after SCI in mice with severe combined immunodeficiency. Finally, the S1P(1) receptor agonist, SEW2871, partly mimicked the therapeutic effect of FTY720. Our data highlight the Importance of immune-independent functions of FTY720 in decreasing vascular permeability and astrogliosis in the injured spinal cord and promoting locomotor function recovery after SCI. (Am J Pathol 2012, 180:1625-1635; DOI: 10.1016/j.ajpath.2011.12.012)