温经通络法外用对奥沙利铂所致周围神经毒性模型干预的研究
发布时间：2018-07-25 20:37
【摘要】：肿瘤发病率逐年增加,临床上化疗药物的使用日益广泛,以奥沙利铂为代表的化疗药物所致的周围神经毒性(Chemotherapy-induced peripheral neurotoxicity, CIPN)成为肿瘤临床难治并发症,该毒性限制了奥沙利铂治疗剂量的提高并降低了患者的生活质量。目前奥沙利铂所致周围神经毒性的发病机制尚不清楚,临床上没有很好的治疗药物,是目前国内外专家关注的难题,需要探索有效可行的解决办法。 目的：拟通过复制奥沙利铂诱导的周围神经毒性大鼠动物模型进一步探讨中医温经通络法外用对周围神经毒性的干预作用；为临床中医药防治化疗周围神经毒性提供有效方法和科学依据。 方法：wistar大鼠50只,随机均等分为5组即正常对照组、模型组、中药低剂量组、中药中剂量组、中药高剂量组。模型组和3个中药组腹腔注射奥沙利铂(乐沙定)3mg/kg,隔天一次,共16次,正常对照组则腹腔注射等体积5%葡萄糖溶液对照；从造模第一天起,3个中药组用对应浓中药煎剂浸泡四肢和尾巴,60min/天,直到造模结束。于第4、8、12、16次注射奥沙利铂后测一次行为学(机械刺激感觉异常,冷刺激过敏反应,热痛缩足潜伏期),末次行为学测试后,戊巴比妥腹腔麻醉测坐骨神经传导速度,采集腹腔静脉血离心取血浆检测NGF,取血处死后取第4、5腰椎背根神经节、坐骨神经及足底皮肤,福尔马林固定,石蜡包埋,切片,HE染色观察背根神经节和坐骨神经形态结构变化,免疫组化染色后,用Image Pro-Plus5.0图像分析软件对背根神经节及足底皮肤P物质进行半定量分析。 结果：各中药组和模型组均出现机械触诱发痛反应,但中药高剂量组的机械触诱发痛反应较模型组动物减少(P0.05)；模型组与正常对照组及各中药组相比冷缩足次数出现明显差异(P0.05)；提示造模成功。模型组和中药高剂量组的坐骨神经传导速度较正常对照组的明显减慢(P0.01,P0.05)；中药高剂量组的坐骨神经传导速度明显快于模型组(P0.05),血清神经生长因子含量中药高剂量组明显高于模型组(P0.05),各中药组间没有明显差异；中药高剂量组组神经元细胞核固缩百分数明显低于模型组,坐骨神经结构改变较模型组轻；足底P物质表达模型组明显增多(P0.01)。 结论：温经通络散能够明显缓解周围神经毒疼痛,加快坐骨神经传导速度,能有效降低奥沙利铂对坐骨神经的损伤。其治疗作用可能是通过保护神经元细胞,缓解坐骨神经损伤,增加血清神经因子表达,减少足底皮肤P物质表达实现的。
[Abstract]:The incidence of cancer is increasing year by year and the use of chemotherapeutic drugs is becoming more and more extensive. The peripheral neurotoxicity caused by oxaliplatin (Chemotherapy-induced peripheral neurotoxicity, CIPN) has become a difficult complication in clinic. This toxicity limits the increase in the dose of oxaliplatin and reduces the quality of life of patients. At present, the pathogenesis of oxaliplatin induced peripheral neurotoxicity is not clear, and there is no good therapeutic drugs in clinic. It is a difficult problem that experts at home and abroad pay attention to, and need to explore effective and feasible solutions. Objective: to explore the effect of warming meridian and dredging collaterals on peripheral nerve toxicity in rats induced by oxaliplatin. To provide effective methods and scientific basis for the prevention and treatment of peripheral neurotoxicity by traditional Chinese medicine. Methods Fifty Wistar rats were randomly divided into 5 groups: normal control group, model group, low dose group, middle dose group and high dose group. The model group and three traditional Chinese medicine groups were intraperitoneally injected with oxaliplatin (3 mg / kg) once every other day for 16 times, while the normal control group was intraperitoneally injected with 5% glucose solution of the same volume. From the first day of making the model, the three groups were soaked in the limbs and tail for 60 min / day with the corresponding concentrated Chinese medicine decoction until the end of the model making. After injection of oxaliplatin on the 4th week, the behavioral changes were measured once (mechanical irritation, cold irritation, hypersensitivity, latent period of foot contraction). After the last behavioral test, intraperitoneal anesthesia of pentobarbital was used to measure the conduction velocity of the sciatic nerve, and the nerve conduction velocities of the sciatic nerve were measured by intraperitoneal anaesthesia of pentobarbital. Blood samples were collected from abdominal venous blood to determine NGF, and the 5th lumbar dorsal root ganglion (DRG), sciatic nerve and plantar skin, formalin fixation, paraffin embedding, and HE staining were used to observe the morphological and structural changes of DRG and sciatic nerve. After immunohistochemical staining, substance P in dorsal root ganglion and plantar skin were semi-quantitatively analyzed by Image Pro-Plus5.0 image analysis software. Results: mechanical tactile induced pain was found in each Chinese medicine group and model group, but the mechanical touch induced pain response in the high dose group was less than that in the model group (P0.05). Compared with the normal control group and the traditional Chinese medicine group, there was a significant difference between the model group and the traditional Chinese medicine group (P0.05), indicating that the model was successful. The conduction velocity of sciatic nerve in the model group and the high dose group was significantly slower than that in the normal control group (P0.01P 0.05). The conduction velocity of sciatic nerve in high dose group of Chinese medicine was significantly faster than that in model group (P0.05), and the content of serum nerve growth factor in high dose group of Chinese medicine was significantly higher than that in model group (P0.05). The percentage of nuclear pyknosis of neurons in the high dose group was significantly lower than that in the model group, the change of sciatic nerve structure was lighter than that in the model group, and the expression of substance P in the plantar of the model group was significantly increased (P0.01). Conclusion: Wenjing Tongluo Powder can obviously relieve the pain of peripheral nerve poison, accelerate the conduction velocity of sciatic nerve, and effectively reduce the injury of oxaliplatin to sciatic nerve. The therapeutic effect may be achieved by protecting neuron cells, relieving sciatic nerve injury, increasing the expression of serum neurofactor and reducing the expression of substance P in plantar skin.
【学位授予单位】：北京中医药大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R273
本文编号：2145012
[Abstract]:The incidence of cancer is increasing year by year and the use of chemotherapeutic drugs is becoming more and more extensive. The peripheral neurotoxicity caused by oxaliplatin (Chemotherapy-induced peripheral neurotoxicity, CIPN) has become a difficult complication in clinic. This toxicity limits the increase in the dose of oxaliplatin and reduces the quality of life of patients. At present, the pathogenesis of oxaliplatin induced peripheral neurotoxicity is not clear, and there is no good therapeutic drugs in clinic. It is a difficult problem that experts at home and abroad pay attention to, and need to explore effective and feasible solutions. Objective: to explore the effect of warming meridian and dredging collaterals on peripheral nerve toxicity in rats induced by oxaliplatin. To provide effective methods and scientific basis for the prevention and treatment of peripheral neurotoxicity by traditional Chinese medicine. Methods Fifty Wistar rats were randomly divided into 5 groups: normal control group, model group, low dose group, middle dose group and high dose group. The model group and three traditional Chinese medicine groups were intraperitoneally injected with oxaliplatin (3 mg / kg) once every other day for 16 times, while the normal control group was intraperitoneally injected with 5% glucose solution of the same volume. From the first day of making the model, the three groups were soaked in the limbs and tail for 60 min / day with the corresponding concentrated Chinese medicine decoction until the end of the model making. After injection of oxaliplatin on the 4th week, the behavioral changes were measured once (mechanical irritation, cold irritation, hypersensitivity, latent period of foot contraction). After the last behavioral test, intraperitoneal anesthesia of pentobarbital was used to measure the conduction velocity of the sciatic nerve, and the nerve conduction velocities of the sciatic nerve were measured by intraperitoneal anaesthesia of pentobarbital. Blood samples were collected from abdominal venous blood to determine NGF, and the 5th lumbar dorsal root ganglion (DRG), sciatic nerve and plantar skin, formalin fixation, paraffin embedding, and HE staining were used to observe the morphological and structural changes of DRG and sciatic nerve. After immunohistochemical staining, substance P in dorsal root ganglion and plantar skin were semi-quantitatively analyzed by Image Pro-Plus5.0 image analysis software. Results: mechanical tactile induced pain was found in each Chinese medicine group and model group, but the mechanical touch induced pain response in the high dose group was less than that in the model group (P0.05). Compared with the normal control group and the traditional Chinese medicine group, there was a significant difference between the model group and the traditional Chinese medicine group (P0.05), indicating that the model was successful. The conduction velocity of sciatic nerve in the model group and the high dose group was significantly slower than that in the normal control group (P0.01P 0.05). The conduction velocity of sciatic nerve in high dose group of Chinese medicine was significantly faster than that in model group (P0.05), and the content of serum nerve growth factor in high dose group of Chinese medicine was significantly higher than that in model group (P0.05). The percentage of nuclear pyknosis of neurons in the high dose group was significantly lower than that in the model group, the change of sciatic nerve structure was lighter than that in the model group, and the expression of substance P in the plantar of the model group was significantly increased (P0.01). Conclusion: Wenjing Tongluo Powder can obviously relieve the pain of peripheral nerve poison, accelerate the conduction velocity of sciatic nerve, and effectively reduce the injury of oxaliplatin to sciatic nerve. The therapeutic effect may be achieved by protecting neuron cells, relieving sciatic nerve injury, increasing the expression of serum neurofactor and reducing the expression of substance P in plantar skin.
【学位授予单位】：北京中医药大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R273
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