Paclitaxel, but Not Cisplatin, Affects Satellite Glial Cells in Dorsal Root Ganglia of Rats with Chemotherapy-Induced Peripheral Neurotoxicity

Chemotherapy-induced peripheral neurotoxicity is one of the most common dose-limiting toxicities of several widely used anticancer drugs such as platinum derivatives (cisplatin) and taxanes (paclitaxel). Several molecular mechanisms related to the onset of neurotoxicity have already been proposed, most of them having the sensory neurons of the dorsal root ganglia (DRG) and the peripheral nerve fibers as principal targets. In this study we explore chemotherapy-induced peripheral neurotoxicity beyond the neuronocentric view, investigating the changes induced by paclitaxel (PTX) and cisplatin (CDDP) on satellite glial cells (SGC) in the DRG and their crosstalk. Rats were chronically treated with PTX (10 mg/Kg, 1qwx4) or CDDP (2 mg/Kg 2qwx4) or respective vehicles. Morpho-functional analyses were performed to verify the features of drug-induced peripheral neurotoxicity. Qualitative and quantitative immunohistochemistry, 3D immunofluorescence, immunoblotting, and transmission electron microscopy analyses were also performed to detect alterations in SGCs and their interconnections. We demonstrated that PTX, but not CDDP, produces a strong activation of SGCs in the DRG, by altering their interconnections and their physical contact with sensory neurons. SGCs may act as principal actors in PTX-induced peripheral neurotoxicity, paving the way for the identification of new druggable targets for the treatment and prevention of chemotherapy-induced peripheral neurotoxicity.

化疗引起的周围神经毒性是诸如铂类衍生物（顺铂）和紫杉烷类（紫杉醇）等广谱抗癌药物最常见的剂量限制性毒性之一。与神经毒性发生相关的多种分子机制已经被提出，其中大部分以背根神经节（DRG）的感觉神经元和周围神经纤维为主要靶点。在本研究中，我们超越了以神经元为中心的视角，探讨了紫杉醇（PTX）和顺铂（CDDP）对DRG中的卫星胶质细胞（SGC）的诱导性变化及其相互作用。大鼠被长期给予PTX（10 mg/Kg，1次/周，连续4周）或CDDP（2 mg/Kg，2次/周，连续4周）或相应的溶剂。通过形态学功能分析以验证药物引起的周围神经毒性的特征。此外，还进行了定性及定量免疫组化、三维免疫荧光、免疫印迹和透射电子显微镜分析，以检测SGC及其相互连接的改变。我们发现，PTX而非CDDP能够显著激活DRG中的SGC，通过改变其相互连接和与感觉神经元之间的物理接触。SGC可能在PTX引起的周围神经毒性中发挥主要作用，为治疗和预防化疗引起的周围神经毒性提供了新的可药物靶向的识别途径。