Distribution and tumor necrosis factor-alpha isoform binding specificity of locally administered etanercept into injured and uninjured rat sciatic nerve.
Distribution and tumor necrosis factor-alpha isoform binding specificity of locally administered etanercept into injured and uninjured rat sciatic nerve.
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DOI：
10.1016/j.neuroscience.2009.02.038
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发表时间：
2009-05-05
期刊：
影响因子：
3.3
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中科院分区：
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肿瘤坏死因子- α (TNF)是一种促炎细胞因子，与神经性疼痛的发生有关。局部施用肿瘤坏死因子拮抗剂依那西普提供了一个有希望的新的治疗方法，以目标神经性疼痛。在这里，我们评估局部给药依那西普在损伤和未损伤大鼠坐骨神经中TNF亚型的分布和结合特异性。局部应用依那西普后1、24、48和96 h，应用免疫组化方法评价依那西普和TNF在损伤和未损伤神经中的分布和共定位。此外，利用免疫印迹检测系统分析依那西普对TNF亚型的结合特异性。一项新的观察发现，局部给药依那西普在给药1小时后到达损伤神经内膜而未到达未损伤神经，主要与tnf阳性结构共定位，形态类似于雪旺细胞和巨噬细胞。我们进一步注意到，依那西普的免疫印迹分析显示其优先结合跨膜和三聚体TNF亚型。最后，局部给药依那西普抑制大鼠坐骨神经挤压模型的疼痛相关行为。我们得出结论，局部给药依那西普到达损伤神经的神经内膜间隙，并优先结合跨膜和生物活性三聚体TNF亚型来调节神经性疼痛。局部给药依那西普有潜力作为一种靶向免疫调节剂治疗周围神经损伤后神经性疼痛的局部发病机制。
Tumor necrosis factor-alpha (TNF) is a pro-inflammatory cytokine that is implicated in the initiation of neuropathic pain. Locally administered TNF antagonist etanercept offers a promising new treatment approach to target neuropathic pain. Here we evaluate the distribution and binding specificity for TNF isoforms of locally administered etanercept into injured and uninjured rat sciatic nerve. Distribution and co-localization of etanercept and TNF in the injured and uninjured nerve was evaluated at 1, 24, 48 and 96 h after etanercept local application using immunohistochemistry. In addition, binding specificity of etanercept for TNF isoforms was analyzed using immunoblot assay system in nerve lysates. A new observation was that locally administered etanercept reached the endoneurium of the injured but not the uninjured nerve 1 h after its application and mainly co-localized with TNF-positive structures, morphologically similar to Schwann cells and macrophages. We further noticed that immunoblot analyses for etanercept demonstrated its preferential binding to transmembrane and trimer TNF isoforms. Finally, locally administered etanercept inhibited pain-related behaviors in a rat sciatic nerve crush model. We conclude that locally administered etanercept reaches the endoneurial space in the injured nerve and preferentially binds to trans-membrane and bioactive trimer TNF isoforms to modulate neuropathic pain. Locally administered etanercept has potential as a targeted immunomodulating agent to treat local pathogenesis in neuropathic pain after peripheral nerve injury.