Platinum-based chemotherapeutics still play an important role in cancer therapy, however, severe side effects, such as painful neuropathy, occur frequently. The pathophysiologic mechanisms depend on the applied chemotherapeutic agent and are still controversial. In addition to neuronal damage, disturbance of glial cell activity may contribute to neurotoxicity. Here, we focused on the effect of oxaliplatin on satellite glial cell (SGC) function and on the activity of the dorsal root ganglion (DRG) neurons. SGCs were isolated as high-purity cultures and treated with 1 and 10 μM oxaliplatin for 2, 4 and 24 h. Subsequently, glial fibrillary acid protein (GFAP), reactive oxygen species (ROS), Connexin-43 (Cx-43), and inward rectifier potassium channel 4.1 (Kir4.1) expression was determined by immunocytochemical staining (ICC) and Western blot analyses. Immunochemical staining and Western blot analysis showed an increase in the immune reactivity (IR) and protein levels of ROS, GFAP, and Cx-43. Furthermore, reduction of the IR and protein levels and current density were demonstrated using patch-clamp measurements, of Kir4.1 channels after oxaliplatin exposure. Cytokine release in SGCs was measured using enzyme-linked immunosorbent assays (ELISA) after oxaliplatin exposure and indicated an increased release of IL-6 and TNFα, while IL-1β was decreased. The direct influence of SGC-secreted factors in the supernatant after oxaliplatin treatment led to the hyperexcitability of cultured DRG neurons. In summary, oxaliplatin has a direct impact on the modulation and function of different SGC proteins. Furthermore, SGC-released factors influence the excitability of sensory neurons, qualifying SGCs as potential targets for the prevention and treatment of oxaliplatin-induced polyneuropathy.

中文翻译：

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奥沙利铂对卫星神经胶质细胞的激活和功能调节导致体外感觉神经元过度兴奋。

铂基化学疗法在癌症治疗中仍然发挥着重要作用，但是，经常会出现严重的副作用，例如神经痛。病理生理机制取决于所应用的化学治疗剂，并且仍存在争议。除神经元损伤外，神经胶质细胞活性的紊乱也可能导致神经毒性。在这里，我们集中于奥沙利铂对卫星神经胶质细胞（SGC）功能的影响以及对背根神经节（DRG）神经元的活性。将SGC分离为高纯度培养物，并用1和10μM奥沙利铂处理2、4和24小时。随后，通过免疫细胞化学染色（ICC）和Western印迹分析确定了神经胶质纤维酸性蛋白（GFAP），活性氧（ROS），连接蛋白43（Cx-43）和内向整流钾通道4.1（Kir4.1）的表达。 。免疫化学染色和蛋白质印迹分析显示，ROS，GFAP和Cx-43的免疫反应性（IR）和蛋白质水平增加。此外，在奥沙利铂暴露后，使用膜片钳测量Kir4.1通道的IR和蛋白质水平以及电流密度降低了。在奥沙利铂暴露后使用酶联免疫吸附测定（ELISA）测定了SGCs中细胞因子的释放，表明IL-6和TNFα的释放增加，而IL-1β减少。奥沙利铂处理后上清液中SGC分泌因子的直接影响导致培养的DRG神经元的过度兴奋。总之，奥沙利铂对不同SGC蛋白的调节和功能具有直接影响。此外，SGC释放的因素会影响感觉神经元的兴奋性，