Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, PR China.
Department of Veterinary Medicine and Animal Science, Beijing University of Agriculture, Beijing, 102206, PR China.
Neuropharmacology. 2021 May 15;189:108535. doi: 10.1016/j.neuropharm.2021.108535. Epub 2021 Mar 23.
Neuregulin-1 (NRG1), a family of EGF-like factors that activates ErbB receptors, can regulate the proliferation, migration, and myelinating of Schwann cells. We previously reported that NRG1/ErbB signal is responsible for organophosphate (OP)-induced delayed neuropathy (OPIDN) in hens, a susceptive animal model to neuropathic organophosphorous compounds. Our previous study discovered that a neuropathic OP, tri-o-cresyl phosphate (TOCP) activated NRG1/ErbB signaling pathway in both spinal cord and sciatic nerves of hens during the formation of OPIDN and lapatinib, a non-selective antagonist of ErbB1 and ErbB2 receptors, alleviated the toxicity. In this study, we intended to further look into the potential role of NRG1 in the pathogenesis of TOCP-induced axon damage in spinal cord and sciatic nerves and whether lapatinib could also rescue this damage in mice, an OPIDN-resistant animal model. The results revealed that no obvious toxic signs were observed after single TOCP exposure. However, slight histopathological wreck in lumbar spinal cord and sciatic nerves was found following TOCP intoxication, and the damage in sciatic nerves was characterized by axon degeneration of myelin sheath but not the loss of neural skeleton. Only histopathological damage induced by TOCP in spinal cord could be prevented by lapatinib. The translational expression of NRG1/ErbB signaling molecules was analyzed by both in vivo and in vitro studies. In general, NRG1/ErbB pathway was activated by TOCP while combined treatment with lapatinib attenuated TOCP-induced NRG1/ErbB signaling cascade. The results implied that NRG1/ErbB system may predominately play functional role in spinal cord (central nervous system) but not in sciatic nerves (peripheral nervous system) of mouse subjected to neurotoxic OP, which was confirmed by the study in vitro that lapatinib was not able to attenuate TOCP-induced neurotoxicity in rodent Schwann cell line RSC 96 cells.
神经调节蛋白 1（NRG1）是一种表皮生长因子样因子家族，可激活 ErbB 受体，能调节雪旺细胞的增殖、迁移和髓鞘形成。我们之前的研究报告指出，NRG1/ErbB 信号通路负责有机磷（OP）诱导的母鸡迟发性神经病（OPIDN），母鸡是一种对神经毒性有机磷化合物敏感的动物模型。我们之前的研究发现，一种神经毒性 OP，三邻甲苯磷酸（TOCP），在 OPIDN 形成过程中激活了母鸡脊髓和坐骨神经中的 NRG1/ErbB 信号通路，而 lapatinib，一种 ErbB1 和 ErbB2 受体的非选择性拮抗剂，减轻了毒性。在这项研究中，我们旨在进一步研究 NRG1 在 TOCP 诱导的脊髓和坐骨神经轴突损伤发病机制中的潜在作用，以及 lapatinib 是否也能挽救 OPIDN 抗性动物模型小鼠中的这种损伤。结果表明，单次接触 TOCP 后没有观察到明显的毒性迹象。然而，在 TOCP 中毒后，发现腰椎脊髓和坐骨神经有轻微的组织病理学损伤，坐骨神经的损伤特征是髓鞘轴突变性，而不是神经骨架的丧失。只有 lapatinib 能预防 TOCP 在脊髓中引起的组织病理学损伤。通过体内和体外研究分析了 NRG1/ErbB 信号分子的翻译表达。总的来说，TOCP 激活了 NRG1/ErbB 通路，而 lapatinib 的联合治疗则减弱了 TOCP 诱导的 NRG1/ErbB 信号级联反应。结果表明，在接受神经毒性 OP 处理的小鼠中，NRG1/ErbB 系统主要在脊髓（中枢神经系统）中发挥功能作用，而不是在坐骨神经（周围神经系统）中发挥作用，这在体外研究中得到了证实，即 lapatinib 不能减轻 TOCP 诱导的啮齿动物雪旺细胞系 RSC 96 细胞的神经毒性。
