Erythropoietin reduces Schwann cell TNF-α, Wallerian degeneration and pain-related behaviors after peripheral nerve injury
Erythropoietin reduces Schwann cell TNF-α, Wallerian degeneration and pain-related behaviors after peripheral nerve injury
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DOI：
10.1111/j.1460-9568.2006.04606.x
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发表时间：
2006-02-01
影响因子：
3.4
通讯作者：
Myers, RR
中科院分区：
文献类型：
--
作者：
Campana, WM;Li, XQ;Myers, RR
慢性坐骨神经压迫性损伤（CCI）可导致Wallerian变性和夸张的疼痛样行为。这些作用在很大程度上是由促炎细胞因子介导的，例如肿瘤坏死因子α（TNF-α）。在这项研究中，我们证明，全身给予重组人促红细胞生成素（rhEpo）促进恢复慢性神经性疼痛与CCI大鼠。由于TNF-α与疼痛相关行为的发展有关，我们测量了神经损伤部位的TNF-α mRNA。与未治疗的动物相比，全身或局部给予rhEpo可降低TNF-α mRNA。RhEpo也能显著减少轴突变性（P < 0.05）。CCI神经免疫组化显示雪旺细胞、轴浆和巨噬细胞中含有丰富的TNF-α。在rhEpo处理的动物中，雪旺细胞中TNF-α免疫阳性选择性降低。这些结果表明，rhEpo通过阻断雪旺细胞中TNF-α的表达来抵消CCI中TNF-α的作用的模型。为了进一步测试该模型，我们研究了原代许旺细胞培养物。RhEpo抑制TNF-α的表达响应脂多糖，支持我们的结论，在体内CCI实验。此外，rhEpo在体外直接对抗由外源性添加的TNF-α诱导的雪旺细胞死亡。这些结果表明，rhEpo通过多种机制调节TNF-α; rhEpo通过许旺细胞调节TNF-α mRNA表达，但也可能直接抵消导致损伤、慢性疼痛和/或死亡的TNF-α信号通路。
Chronic sciatic nerve constriction injury (CCI) induces Wallerian degeneration and exaggerated pain-like behaviors. These effects are mediated in large part by pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha). In this study, we demonstrate that systemically administered recombinant human erythropoietin (rhEpo) facilitates recovery from chronic neuropathic pain associated with CCI in rats. Because TNF-alpha has been implicated in the development of pain-related behaviors, we measured TNF-alpha mRNA at the nerve injury site. Systemically or locally administered rhEpo decreased TNF-alpha mRNA, compared with that observed in untreated animals. RhEpo also significantly (P < 0.05) decreased axonal degeneration. Immunohistochemistry of CCI nerve showed abundant TNF-alpha in Schwann cells, axoplasm and macrophages. In rhEpo-treated animals, TNF-alpha immunopositivity was decreased selectively in Schwann cells. These results suggest a model in which rhEpo counteracts the effects of TNF-alpha in CCI by blocking expression of TNF-alpha in Schwann cells. To further test this model, we studied primary Schwann cell cultures. RhEpo inhibited TNF-alpha expression in response to lipopolysaccharide, supporting the conclusions of our in vivo CCI experiments. In addition, rhEpo directly counteracted Schwann cell death induced by exogenously added TNF-alpha in vitro. These results indicated that rhEpo regulates TNF-alpha by multiple mechanisms; rhEpo regulates TNF-alpha mRNA expression by Schwann cells but also may directly counteract TNF-alpha signaling pathways that lead to injury, chronic pain and/or death.