Li Yan, Zhang Haijun, Zhang Hongmei, Kosturakis Alyssa K, Jawad Abdul Basit, Dougherty Patrick M
Department of Anesthesia and Pain Medicine Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
University of Texas Health Science Center, Houston, Texas.
J Pain. 2014 Jul;15(7):712-25. doi: 10.1016/j.jpain.2014.04.001. Epub 2014 Apr 19.
This paper tests the contribution of the toll-like receptors, TLR4 in particular, in the initiation and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy. TLR4 and its immediate downstream signaling molecules-myeloid differentiation primary response gene 88 (MyD88) and toll/interleukin 1 receptor domain-containing adapter-inducing interferon-β (TRIF)-were found to be increased in the dorsal root ganglion (DRG) using Western blot by day 7 of paclitaxel treatment. The behavioral phenotype, the increase of both TLR4 and MyD88, was blocked by cotreatment with the TLR4 antagonist lipopolysaccharide-Rhodobacter sphaeroides during chemotherapy. A similar, but less robust, behavioral effect was observed using intrathecal treatment of MyD88 homodimerization inhibitory peptide. DRG levels of TLR4 and MyD88 reduced over the next 2 weeks, whereas these levels remained increased in spinal cord through day 21 following chemotherapy. Immunohistochemical analysis revealed TLR4 expression in both calcitonin gene-related peptide-positive and isolectin B4-positive small DRG neurons. MyD88 was only found in calcitonin gene-related peptide-positive neurons, and TRIF was found in both calcitonin gene-related peptide-positive and isolectin B4-positive small DRG neurons as well as in medium- and large-size DRG neurons. In the spinal cord, TLR4 was only found colocalized to astrocytes but not with either microglia or neurons. Intrathecal treatment with the TLR4 antagonist lipopolysaccharide-R. sphaeroides transiently reversed preestablished chemotherapy-induced peripheral neuropathy mechanical hypersensitivity. These results strongly implicate TLR4 signaling in the DRG and the spinal cord in the induction and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy.
The toll-like receptor TLR4 and MyD88 signaling pathway could be a new potential therapeutic target in paclitaxel-induced painful neuropathy.
本文测试了Toll样受体，特别是TLR4，在紫杉醇相关化疗诱导的周围神经病变的起始和维持中的作用。通过蛋白质免疫印迹法发现，在紫杉醇治疗第7天时，背根神经节（DRG）中的TLR4及其直接下游信号分子——髓样分化初级反应基因88（MyD88）和含Toll/白细胞介素1受体结构域的衔接蛋白诱导干扰素-β（TRIF）增加。在化疗期间，用TLR4拮抗剂脂多糖-球形红细菌共同处理可阻断行为表型以及TLR4和MyD88的增加。使用鞘内注射MyD88同二聚化抑制肽观察到类似但较弱的行为效应。在接下来的2周内，DRG中TLR4和MyD88的水平降低，而在化疗后第21天，脊髓中的这些水平仍保持升高。免疫组织化学分析显示，在降钙素基因相关肽阳性和异凝集素B4阳性的小DRG神经元中均有TLR4表达。MyD88仅在降钙素基因相关肽阳性神经元中发现，而TRIF在降钙素基因相关肽阳性和异凝集素B4阳性的小DRG神经元以及中、大型DRG神经元中均有发现。在脊髓中，仅发现TLR4与星形胶质细胞共定位，而与小胶质细胞或神经元均无共定位。用TLR4拮抗剂脂多糖-球形红细菌进行鞘内治疗可短暂逆转先前建立的化疗诱导的周围神经病变机械性超敏反应。这些结果强烈表明，DRG和脊髓中的TLR4信号传导在紫杉醇相关化疗诱导的周围神经病变的诱导和维持中起作用。
Toll样受体TLR4和MyD88信号通路可能是紫杉醇诱导的疼痛性神经病变的新潜在治疗靶点。
