Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany.
Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany.
Exp Neurol. 2021 Jul;341:113695. doi: 10.1016/j.expneurol.2021.113695. Epub 2021 Mar 14.
Cisplatin plays an essential role in the treatment of various cancers. Cisplatin exhibits high efficacy, but it often leads to severe neurotoxic side effects, such as chemotherapy-induced polyneuropathy (CIPN). The pathophysiology of CIPN is not fully understood. There is increasing evidence for damage to satellite glial cells (SGC) and dorsal root ganglion (DRG) neurons. We investigated the influence of cisplatin on the function of SGCs and the direct influence on DRGs. Satellite glial cells were isolated from DRG and exposed to 0.1, 1, 10, or 100 μM cisplatin for 2 h, 4 h, and 24 h. Using immunocytochemical staining and Western blot analysis, the expression of the glial fibrillary acid protein (GFAP), reactive oxygen species (ROS), and inward rectifier potassium channel 4.1 (K) was determined. An increase in the immune reactivity (IR) and protein levels of GFAP and ROS was measured, and a reduction of IR and protein level of K was detected. A decrease in these channels' current density was observed using the whole-cell patch-clamp recording. The interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) release of SGCs increased after cisplatin exposure as measured using ELISA, and interleukin-1β (IL-1β) decreased. The SGC-secreted factors in the supernatant after cisplatin treatment led to a modulation of cultured DRG neurons' excitability. Taken together, the modulation and function of different SGC proteins could be linked to a direct impact of cisplatin. Further, SGC-secreted factors influenced the excitability of sensory neurons. Overall, SGCs could be a potential target in preventing and treating chemotherapy-induced neuropathic pain.
顺铂在各种癌症的治疗中起着重要作用。顺铂疗效高，但常导致严重的神经毒性副作用，如化疗诱导的多发性神经病（CIPN）。CIPN 的病理生理学尚未完全阐明。越来越多的证据表明卫星胶质细胞（SGC）和背根神经节（DRG）神经元受损。我们研究了顺铂对 SGC 功能的影响及其对 DRG 的直接影响。从 DRG 中分离出卫星胶质细胞，用 0.1、1、10 或 100μM 顺铂分别孵育 2、4 和 24 小时。通过免疫细胞化学染色和 Western blot 分析，测定胶质纤维酸性蛋白（GFAP）、活性氧（ROS）和内向整流钾通道 4.1（K）的表达。测量 GFAP 和 ROS 的免疫反应性（IR）和蛋白水平增加，以及 K 的 IR 和蛋白水平降低。使用全细胞膜片钳记录测量这些通道的电流密度降低。ELISA 检测到顺铂暴露后 SGC 中白细胞介素 6（IL-6）和肿瘤坏死因子 α（TNFα）的释放增加，白细胞介素 1β（IL-1β）减少。顺铂处理后 SGC 上清液中分泌的因子导致培养的 DRG 神经元兴奋性发生调制。总之，不同 SGC 蛋白的调节和功能可能与顺铂的直接影响有关。此外，SGC 分泌的因子影响感觉神经元的兴奋性。总的来说，SGC 可能是预防和治疗化疗诱导的神经性疼痛的潜在靶点。
