Chemotherapy-induced peripheral neuropathy is promoted by enhanced spinal insulin-like growth factor-1 levels via astrocyte-dependent mechanisms
Chemotherapy-induced peripheral neuropathy is promoted by enhanced spinal insulin-like growth factor-1 levels via astrocyte-dependent mechanisms
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化疗引起的周围神经病变是通过星形胶质细胞依赖性机制增强脊髓胰岛素样生长因子-1 水平而促进的。
DOI：
10.1016/j.brainresbull.2021.07.026
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发表时间：
2021-08-02
影响因子：
3.8
通讯作者：
Wang, Han-bing
中科院分区：
文献类型：
--
作者：
Le, Yue;Chen, Xin;Wang, Han-bing
背景：化疗引起的周围神经病变（CIPN）是化疗患者常见且难治的并发症。胰岛素样生长因子-1（IGF-1）是一种常见的神经营养因子，具有多种功能，如维持中枢神经系统中神经元的存活和突触功能。因此，我们假设IGF-1信号通路可能是治疗CIPN的候选靶点。研究方法：我们通过腹腔注射奥沙利铂建立了CIPN模型，并通过Western印迹和免疫荧光法评估了腰髓中IGF-1蛋白表达及其受体IGF 1 R、磷酸化IGF 1 R（p-IGF 1 R）、白细胞介素-17 A（IL-17 A）、肿瘤坏死因子-α（TNF-α）和降钙素基因相关肽（CGRP）。为了研究IGF-1信号传导对CIPN的影响，我们向小鼠鞘内或腹膜内注射小鼠重组IGF-1（rIGF-1）。结果如下：在D3和D10（开始奥沙利铂化疗后第3天和第10天），IGF-1蛋白表达在脊髓中显著降低，并且主要与腰髓中的星形胶质细胞共定位，而IGF 1 R主要在神经元上表达。鞘内和腹腔内注射rIGF-1均缓解了化疗诱导的疼痛样行为，并降低了脊髓中IL-17 A、TNF-α和CGRP蛋白的表达。结论：我们的研究结果表明IGF-1信号在CIPN中起着重要作用。靶向IGF-1信号传导可能是在临床环境中治疗CIPN的有效治疗策略。
Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and intractable complication in chemotherapy-receiving patients. Insulin-like growth factor-1 (IGF-1) is a popular neurotrophin with various functions, such as maintaining neuronal survival and synaptic functioning in the central nervous system. Therefore, we hypothesized that the IGF-1 signaling pathway could be a candidate target for treating CIPN. Methods: We established the CIPN model by injecting mice intraperitoneally with oxaliplatin and assessed IGF-1 protein expression, its receptor IGF1R, phospho-IGF1R (p-IGF1R), interleukin-17A (IL-17A), tumor necrosis factor-alpha (TNF-alpha), and calcitonin gene-related peptide (CGRP) in the lumbar spinal cord with Western blot and immunofluorescence. To examine the effect of IGF-1 signaling on CIPN, we injected mice intrathecally or intraperitoneally with mouse recombinant IGF-1 (rIGF-1). Results: IGF-1 protein expression decreased significantly in the spinal cord on D3 and D10 (the 3rd and 10th days after beginning oxaliplatin chemotherapy) and was co-localized with astrocytes primarily in the lumbar spinal cord, whereas IGF1R was predominantly expressed on neurons. Both intrathecally-and intraperitoneallyadministered rIGF-1 relieved the chemotherapy-induced pain-like behavior and reduced IL-17A, TNF-alpha, and CGRP protein expressions in the spinal cord. Conclusion: Our results indicate a vital role for IGF-1 signaling in CIPN. Targeting IGF-1 signaling could be a potent therapeutic strategy for treating CIPN in clinical settings.