紫杉醇相关外周神经毒性反应发生的相关影响因素及作用机制研究

Influencing Factors and Mechanism of Paclitaxel-related Peripheral Neurotoxic Reactions

目的:探讨紫杉醇相关外周神经毒性(PIPN)反应发生的相关影响因素及其具体作用机制。方法:选取30只成年雄性Wister大鼠作为研究对象,采用随机数字表法将其分为空白对照组与紫杉醇组,每组15只。紫杉醇组实验第1、5、9、13天向大鼠腹腔内注射紫杉醇8 mg/kg,空白对照组则在相同时间予以等容量生理盐水腹腔注射,观察两组大鼠注射前1 d及实验第6、14天外周神经损伤情况,并在末次注射后次日处死大鼠观察坐骨神经结构、测定血清神经生长因子(NGF)水平。结果:实验第14天,紫杉醇组大鼠机械缩足反射阈值(MWT)与热缩足潜伏期(TWL)较注射前1 d、实验第6天及空白对照组均明显升高,且实验第6天MWT、TWL均明显高于注射前1 d与空白对照组,差异均有统计学意义(P<0.05)。实验第14天,紫杉醇组大鼠IL-6、IL-1β及TNF-α水平均明显高于空白对照组,差异均有统计学意义(P<0.05)。镜下观察紫杉醇组大鼠坐骨神经纤维结构存在明显的破坏,髓鞘肿胀、碎裂,线粒体结构破坏,基质结构紊乱等表现。紫杉醇组实验第14天NGF水平均明显低于注射前1 d及空白对照组,差异均有统计学意义(P<0.05)。结论:紫杉醇可对外周神经结构的完整性产生一定的破坏作用,随着用药时间的延长表现为进行性的外周神经功能障碍与缺损,其可能与外周神经元细胞内促炎细胞因子有关,但其确切机制仍未完全明确。

Objective:To explore the related factors and specific mechanisms of Paclitaxel-induced peripheral neurotoxicity (PIPN).Method:Thirty adult male Wister rats were selected as the research objects.Fifteen rats in Paclitaxel group were intraperitoneally injected with 8 mg/kg Paclitaxel on the 1st,5th,9th and 13th day of the experiment,while the blank control group was intraperitoneally injected with the same volume of normal saline at the same time,the rats were killed on the 6th,14th day of experiment to observe the sciatic nerve structure and determine the level of serum nerve growth factor (NGF).Result:The mechanical paw retraction reflex threshold (MWT) and thermal paw retraction latency (TWL) of Paclitaxel group on the 14th day of experiment were significantly higher than those at 1 d before injection,on the 6th day of experiment and blank control group,and the MWT and TWL on the 6th day of experiment were significantly higher than those at 1 d before injection and blank control group (P<0.05).The levels of IL-6,IL-1β and TNF-α in Paclitaxel group on the 14th day of experiment were significantly higher than those in blank control group,there were significant differences (P<0.05).Microscopically,the sciatic nerve fiber structure of paclitaxel group significantly damaged,myelin swelling,fragmentation,mitochondrial structure damage,matrix structure disorder.On the 14th day of experiment,the level of NGF of Paclitaxel group was significantly lower than those of 1 d before injection and blank control group (P<0.05).Conclusion:Paclitaxel can damage the integrity of peripheral nerve structure to a certain extent,with the prolongation of treatment time,Paclitaxel shows progressive peripheral nerve dysfunction and defect.