Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice.
Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice.
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DOI：
10.1186/s12974-014-0159-6
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发表时间：
2014-09-10
影响因子：
9.3
通讯作者：
Bethea JR
中科院分区：
文献类型：
--
作者：
Novrup HG;Bracchi-Ricard V;Ellman DG;Ricard J;Jain A;Runko E;Lyck L;Yli-Karjanmaa M;Szymkowski DE;Pearse DD;Lambertsen KL;Bethea JR
中枢神经系统（CNS）中神经胶质细胞活化和炎症介质的过度产生与CNS的急性创伤性损伤（包括脊髓损伤（SCI））有关。在损伤后早期，在损伤的脊髓中发现促炎细胞因子肿瘤坏死因子（TNF）水平升高，其以可溶性（sol）和跨膜（tm）形式存在。然而，solTNF与tmTNF对病变发展的贡献仍不清楚。我们测试了使用XPro 1595单独全身或中枢阻断solTNF的效果，与使用药物依那西普阻断solTNF和tmTNF相比，在小鼠中度SCI后使用安慰剂载体。使用Basso小鼠量表、行走试验和热痛觉过敏分析评价功能结局。用免疫组化和蛋白质印迹分析研究损伤脊髓的炎症反应。我们发现，外周给予抗TNF治疗对SCI后的运动表现没有明显影响。相比之下，XPro 1595的中央给药导致运动功能改善，焦虑相关行为减少，并减少对受损脊髓的损伤，而依那西普的中央给药没有治疗作用。XPro 1595治疗小鼠的改善伴随着Toll样受体4和TNF受体2（TNFR 2）蛋白水平的增加以及SCI后7天和28天小胶质细胞/巨噬细胞中Iba 1蛋白表达的变化。这些研究表明，通过选择性阻断solTNF，XPro 1595在直接应用于受损脊髓时具有神经保护作用。这种保护可能是通过改变炎症环境介导的，而不抑制通过TNFR 2的tmTNF信号传导的神经保护作用。
Glial cell activation and overproduction of inflammatory mediators in the central nervous system (CNS) have been implicated in acute traumatic injuries to the CNS, including spinal cord injury (SCI). Elevated levels of the proinflammatory cytokine tumor necrosis factor (TNF), which exists in both a soluble (sol) and a transmembrane (tm) form, have been found in the lesioned cord early after injury. The contribution of solTNF versus tmTNF to the development of the lesion is, however, still unclear. We tested the effect of systemically or centrally blocking solTNF alone, using XPro1595, versus using the drug etanercept to block both solTNF and tmTNF compared to a placebo vehicle following moderate SCI in mice. Functional outcomes were evaluated using the Basso Mouse Scale, rung walk test, and thermal hyperalgesia analysis. The inflammatory response in the lesioned cord was investigated using immunohistochemistry and western blotting analyses. We found that peripheral administration of anti-TNF therapies had no discernable effect on locomotor performances after SCI. In contrast, central administration of XPro1595 resulted in improved locomotor function, decreased anxiety-related behavior, and reduced damage to the lesioned spinal cord, whereas central administration of etanercept had no therapeutic effects. Improvements in XPro1595-treated mice were accompanied by increases in Toll-like receptor 4 and TNF receptor 2 (TNFR2) protein levels and changes in Iba1 protein expression in microglia/macrophages 7 and 28 days after SCI. These studies suggest that, by selectively blocking solTNF, XPro1595 is neuroprotective when applied directly to the lesioned cord. This protection may be mediated via alteration of the inflammatory environment without suppression of the neuroprotective effects of tmTNF signaling through TNFR2.
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影响因子：
15.3
作者：
Brambilla, R;Bracchi-Ricard, V;Hu, WH;Frydel, B;Bramwell, A;Karmally, S;Green, EJ;Bethea, JR
通讯作者：
Bethea, JR
影响因子：
14.5
作者：
Brambilla, Roberta;Ashbaugh, Jessica Jopek;Bethea, John R.
通讯作者：
Bethea, John R.
影响因子：
5.3
作者：
Kim, GM;Xu, J;Hsu, CY
通讯作者：
Hsu, CY
影响因子：
13.8
作者：
Goffe, B;Cather, JC
通讯作者：
Cather, JC
DOI：
10.1523/jneurosci.3257-09.2009
发表时间：
2009-10-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kigerl KA;Gensel JC;Ankeny DP;Alexander JK;Donnelly DJ;Popovich PG
通讯作者：
Popovich PG