Novel sinomenine derivative 1032 improves immune suppression in experimental autoimmune encephalomyelitis
Novel sinomenine derivative 1032 improves immune suppression in experimental autoimmune encephalomyelitis
复制标题
新型青藤碱衍生物1032改善实验性自身免疫性脑脊髓炎的免疫抑制
DOI：
10.1016/j.bbrc.2009.12.028
复制
发表时间：
2010-01-01
影响因子：
3.1
通讯作者：
Sun, Bing
中科院分区：
文献类型：
--
作者：
Yan, Ling-Chen;Bi, En-Guang;Sun, Bing
青藤碱（Sinomenine，SIN）是从中药青风藤（Sinomenium acutum）中分离得到的一种生物碱。它被广泛用作治疗自身免疫性疾病的免疫抑制药物。大剂量治疗因其疗效差，存在一定的毒副作用，限制了其进一步的应用。本研究采用化学修饰的方法来提高SIN的体内外治疗效果。青藤碱的一个新衍生物，命名为1032，表现出显着改善其母体天然化合物（SIN）的免疫抑制活性。在实验性自身免疫性脑脊髓炎（EAE）模型中，1032显著降低致脑炎性T细胞应答并诱导EAE的改善，其结果与其对IL-17产生的选择性抑制作用有关。相比之下，SIN治疗仅导致EAE严重程度的中度缓解，并且IL-17的表达水平没有显著降低。此外，1032表现出对Th 17细胞分化的抑制，而不是Treg细胞分化，这一结果可能与其对I κ B-α的抑制作用有关。降解以及对BMDC中IL-6和TNF-α分泌的影响。我们推测1032作为一种新型抗炎剂可能靶向DC以阻断IL-6的产生，这反过来又会终止Th 17细胞的发育。因此，SIN衍生物1032在用于治疗自身免疫性和炎性疾病的新药开发中呈现出相当大的潜力。(C)2009 Elsevier Inc. All rights reserved.
Sinomenine (SIN) is an alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating autoimmune diseases. Due to its poor efficiency, the large-dose treatment presents some side effects and limits its further applications. In this study, we used chemical modification to improve the therapeutic effect of SIN in vitro and in vivo. A new derivative of sinomenine, named 1032, demonstrates significantly improved immunosuppressive activity over that of its parent natural compound (SIN). In an experimental autoimmune encephalomyelitis (EAE) model, 1032 significantly reduced encephalitogenic T cell responses and induced amelioration of EAE, which outcome was related to its selective inhibitory effect on the production of IL-17. By contrast, SIN treatment only led to a moderate alleviation of EAE severity and the expression level of IL-17 was not significantly reduced. Furthermore, 1032 exhibited suppression of Th17, but not Treg, cell differentiation, a result probably related to its inhibitory effect on I kappa B-alpha. degradation as well as on IL-6 and TNF-alpha secretion in BMDCs. We speculate that 1032 as a novel anti-inflammatory agent may target DC to block IL-6 production, which in turn would terminate Th17 cell development. Thus, SIN derivative 1032 presents considerable potential in new drug development for treating autoimmune and inflammatory disease. (C) 2009 Elsevier Inc. All rights reserved.