还原型谷胱甘肽对奥沙利铂致大鼠周围神经毒性保护作用病理学研究

目的探讨奥沙利铂致大鼠周围神经毒性作用机制及还原型谷胱甘肽（GSH）对其毒性的影响。方法健康雄性Wistar大鼠120只,随机分成对照组、奥沙利铂组、还原型谷胱甘肽组;对照组大鼠腹腔注射5%葡萄糖30ml.kg-1、奥沙利铂组和GSH组腹腔注射奥沙利铂20mg.kg-1＋5%葡萄糖30ml.kg-1、奥沙利铂20mg.kg-1＋GSH500 mg.kg-1＋5%葡萄糖30 ml.kg-1;观测各组实验大鼠的中毒状况;用光镜技术、免疫组织化学染色观察雄性大鼠后根神经节内的感觉神经元的损伤情况,并用图像分析系统对神经元胞体、胞核、以及核仁的形态学变化及神经生长因子免疫阳性细胞的平均吸光度进行测定。结果与对照组比较,奥沙利铂损伤的主要靶器官为大鼠后根神经节内感觉神经元,神经元核仁、胞核、胞体面积及NGF吸光度显著减小,第2天最明显,6周左右恢复。与奥沙利铂组比较,GSH组的神经元核仁、胞核、胞体面积及NGF吸光度减小改善,2周左右恢复。奥沙利铂组大鼠后根神经节神经元胞质皱缩,核仁偏心,GSH组的损伤相对较轻,有所好转。结论奥沙利铂可导致大鼠周围感觉神经神经元受损,注射外源性GSH可以减轻其损伤作用。

Relief of oxaliplatin-induced peripheral neurotoxicity with reduced glutathione administration

Objective To evaluate whether reduced glutathione （GSH） relieves the peripheralneurotoxicityoxaliplatin induced. Methods Wistar rats were randomly assigned into one of three groups： control, oxaliplatin and GSH group, the rats in the control group were abdominally injected with 5 % glucose 30 ml＇kg^-l.The oxaliplatin-treated rats were abdominally injected with oxaliplatin 20 mg＇kg-1. The GSH-treated rats were added on abdominally injection of GSH 500 mg＇kg＇1in addition to the regimen oxaliplatin-treated rats were administered for abdominally injection. The effectiveness of the treatment was assessed based on the improvements of toxic symptoms and signs, including DRG sensory neurons and sciatic nerves of all rats were studied by the light microscopy and transmission electron microscopy technique to define the pathological changes. The expression of NGF in DR（} was detected by immunohistochemistry. DRG sensory neurons and the expression of NGF were analyzed by Digital Medical Image Analysis System to determine the morphologhical changes of DRG and the expression of NGF. Results Compared to the control group, in the period of oxaliplatin treatment, DRG was the main target of the peripheral neurotoxicity. The nucleolus showed the most prominent pathological changes. The neuropathological examination evidenced shrinkage of DRG soma, nucleus, nuclenlus and the NGF expression were shown in the treated rats. All these changes were evident at 48 hours and almost completely recovered in 6 weeks. Compared to the oxaliplatin group, all these changes were evident were improved, and were recovered at 2 weeks. The dorsal root ganglion in oxaliplatin group showed more severity of kytoplasm shrinkage with eccentric nucleoli and nuclear fagmentatinn than in the GSH group. Conclusion The damages of the peripheral sensory nerve by oxaliplatin might be reversed by the injection of GSH.