促红细胞生成素及其受体在脊髓与周围神经系统中表达及作用的实验研究
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摘要
第一部分:大鼠坐骨神经、脊神经节和脊髓中EPO及EPOR的表达及坐骨神经损伤后表达的变化
目的观察大鼠正常坐骨神经、脊神经节与脊髓中促红细胞生成素(EPO)及其受体(EPOR)的表达及坐骨神经损伤后表达的变化。
方法取成年雄性SD大鼠36只,随机分成:正常组、对照组和损伤组第1d、7d、14d、28d时间组,共6组,每组6只。损伤组钳夹损伤双侧坐骨神经。于术后第1d、7d、14d、28d取各组腰4～腰6节段脊髓、相对应脊神经节组织和坐骨神经,采用免疫组织化学Envision法和逆转录-聚合酶链式反应(RT-PCR)法检测与图像分析技术,对EPO及EPOR的表达进行检测与分析。
结果大鼠正常坐骨神经和损伤的坐骨神经均存在EPO及其受体的表达;正常脊神经节中可见EPO及EPOR的强表达,坐骨神经损伤后脊神经节中仍有EPO及EPOR的表达,其中EPO在脊神经节中表达增强,而EPOR的表达减弱;正常脊髓前角运动神经元和坐骨神经损伤后脊髓前角运动神经元均未见EPO表达,EPOR在正常脊髓前角运动神经元和坐骨神经损伤后脊髓前角运动神经元均可见EPOR表达。
结论本实验从中枢神经元的角度揭示EPO促进周围神经再生机制,为今后进一步应用EPO治疗周围神经损伤奠定了实验及理论基础。
第二部分:靶肌肉注射促红细胞生成素对大鼠周围神经再生的作用
目的探讨靶肌肉注射人重组促红细胞生成素(recombinant human erythropoietin ,rh-EPO)对大鼠坐骨神经损伤后神经再生的作用。
方法选用健康雄性SD大鼠12只,制备大鼠右侧坐骨神经钳夹损伤模型。实验动物随机分为2组,每组6只,EPO组:靶肌肉注射rh-EPO 2500U/kg;对照组:注射同体积的生理盐水。术后第7d、14d、21d观察坐骨神经功能指数(SFI),第21d检测右小腿腓肠肌湿重及组织学观察脊髓腰膨大(L4～L6)、夹伤远端坐骨神经、损伤侧腓肠肌组织并作图象分析测定脊髓前角运动神经元数、再生有髓神经纤维数、髓鞘厚度、轴突直径和腓肠肌肌细胞截面积等指标。
结果术后第7d两组SFI无显著性差异,术后第14d、21d EPO组SFI恢复程度明显大于对照组,差别有显著性意义(P<0.05);术后第21d右小腿腓肠肌肌湿重(mg),EPO组为554.27±51.96(mg),与对照组451.67±66.79(mg)比较差异有显著性意义(P<0.05);术后第21d损伤侧脊髓前角运动神经元数、再生有髓神经纤维数、髓鞘厚度、轴突直径和腓肠肌肌细胞截面积等指标,EPO组均优于对照组(P<0.05,P<0.01)。结论靶肌肉注射rh-EPO能促进周围神经再生和功能恢复。
第三部分:外源性促红细胞生成素对失神经肌肉萎缩的影响
目的探讨外源性促红细胞生成素对失神经支配肌肉的影响。
方法SD大鼠24只,在梨状肌下缘切断坐骨神经,制作小腿三头肌失神经支配模型。实验动物随机分为EPO组(n=12)和对照组(n=12), EPO组于术后小腿腓肠肌内注射rh-EPO2500U/kg;对照组小腿腓肠肌内注射等量生理盐水;每天注射一次。于术后第2、4周检测两组肌湿重、肌肉蛋白含量、肌细胞直径和横切面积,肌肉Na~+-K~+-ATP酶和Ca~(2+)-ATP酶活性及骨骼肌细胞凋亡率变化。
结果术后第2、4周EPO组肌湿重、肌肉蛋白含量、肌细胞直径和横切面积,肌肉Na~+-K~+-ATP酶和Ca~(2+)-ATP酶活性均明显高于对照组(P<0.05),而EPO组肌细胞凋亡数明显低于对照组(P<0.05)。
结论外源性EPO具有明显延缓失神经肌肉萎缩的作用。
Part one: Expression of EPO and its receptors in the spinal cord、dorsal root ganglia and sciatic nerve and their changes after injury of rat sciatic nerves
Objective To investigate the expression and the pattern of EPO and its receptors (EPOR) in the spinal cord, the dorsal root ganglia and the sciatic nerve after sciatic nerves crushed injury in rats.
Methods Thirty-six male adult Sprague-Dawley rats were divided randomly into normal group,control group and experimental group. The rats of experimental group were received crushed to bilateral sciatic nerves and L4～L6 spinal cords , dorsal root ganglias and sciatic nerves were harvested respectively at 1d,7d,14d and 28d after operation. Immunohistochemical method and Reverse Transcription-Polymerase Chain Reaction (RT-PCR) for erythropoietin and erythropoietin receptor and image analysis were used to observe the expression of EPO and EPOR.
Results EPO and EPOR were present in uninjured and injured sciatic nerves. They were also expressed in normal dorsal root ganglias. After crush injury, EPO expression is increased and EPOR is decreased.EPO immunostaining and RT-PCR were unoberserved in motor neurons of spinal cord in normal group and experimental group,however, EPOR were noted in motor neurons of spinal cord in normal group and after sciatic nerves crush injury.
Conclusion The results reveal the favorable effects of EPO on nerve regeneration from the angles of central neurons, which establishes the experimental and theoretical foundation in the further treating peripheral nerve injuries with EPO.
Part two: Effect of target muscle injection of recombinant human erythropoietin on peripheral nerve regeneration in rats
Objective To investigate the effect of target muscle injection of recombinant human erythropoietin(rh-EPO)on the nerve regeneration of adult rats sciatic nerves. Methods 12 healthy male Sprague-Dawley rats were involved and right sciatic nerve crushed model was used.The experimental rats were divided randomly into two groups: the EPO group and the control group, 6 rats in each group. Rh-EPO 2500U/kg was injected daily into the gastrocnemius in EPO group , and normal saline was injected into the gastrocnemius every day after operation in control group. At days 7、14 and 21 after operation, the sciatic function index (SFI) was determined by walking tract analysis. At 21 days after operation,the muscle wet weights were measured,and the spinal cord segments (L4～L6 ),the distal site of injured sciatic nerve and the injured gastrocnemius muscle were observed by light microscope.The count of motor neurons of anterior horn , the number of myelinated fibers , the cross section areas of gastrocnemius muscle cells and other parameters were determined.
Results At day 7 after operation , SFI scores had no significant difference between two groups;at day 14 and 21 after operation ,SFI score of EPO group was significantly higher than that of the control group(P<0.01). At day 21 after operation,the gastrocnemius muscle wet weights in the EPO group and the control group were 554.27±51.96(mg) and 451.67±66.79(mg) respectively, with significant difference between the EPO group and the control group(P<0.05). The numbers of motor neurons of anterior horn, myelinated nerve fibers,diameter of axon,thick of myelin sheath and the cross section areas of gastrocnemius muscle cells in EPO group were significantly superior to those in control group(P< 0.05 ,P<0.01).
Conclusion Target muscle injected rh-EPO can promote the injured nerve regeneration and improve the recovery of their function.
Part three: The effect of exogenous erythropoietin on the denervated muscle atrophy Objective To study the effect of exogenous recombinant human EPO (rh-EPO)on the denervated muscular atrophy.
Methods 24 male Sprague-Dawley rats were involved. Model of denervated gastrocnemius muscle was set up after sciatic nerves were transected at the right lower limb. The rats were randomly divided into two groups: the EPO group and the control group. Rh-EPO 2500U/kg was injected daily into the denervated gastrocnemius in EPO group , and normal saline was injected into the denervated gastrocnemius in control group.At 2 and 4 weeks after operation, the muscle wet weight, the muscle cell diameter and cross section areas, the protein amount, the percentage of the apoptotic muscle cells and Na~+-K~+-ATPase and Ca~(2+)-ATPase activities were observed.
Results At 2 and 4 weeks after operation, the muscle wet weight, Na~+-K~+-ATPase and Ca~(2+)-ATPase activities,the muscle cell diameter and cross section areas and the protein amount were significantly greater in EPO group than those in control group, however, the percentage of the apoptotic muscle cells was significantly smaller in EPO group than that in control group .
Conclusions Exogenous erythropoietin can delay the denervated muscle atrophy.
目的观察大鼠正常坐骨神经、脊神经节与脊髓中促红细胞生成素(EPO)及其受体(EPOR)的表达及坐骨神经损伤后表达的变化。
方法取成年雄性SD大鼠36只,随机分成:正常组、对照组和损伤组第1d、7d、14d、28d时间组,共6组,每组6只。损伤组钳夹损伤双侧坐骨神经。于术后第1d、7d、14d、28d取各组腰4～腰6节段脊髓、相对应脊神经节组织和坐骨神经,采用免疫组织化学Envision法和逆转录-聚合酶链式反应(RT-PCR)法检测与图像分析技术,对EPO及EPOR的表达进行检测与分析。
结果大鼠正常坐骨神经和损伤的坐骨神经均存在EPO及其受体的表达;正常脊神经节中可见EPO及EPOR的强表达,坐骨神经损伤后脊神经节中仍有EPO及EPOR的表达,其中EPO在脊神经节中表达增强,而EPOR的表达减弱;正常脊髓前角运动神经元和坐骨神经损伤后脊髓前角运动神经元均未见EPO表达,EPOR在正常脊髓前角运动神经元和坐骨神经损伤后脊髓前角运动神经元均可见EPOR表达。
结论本实验从中枢神经元的角度揭示EPO促进周围神经再生机制,为今后进一步应用EPO治疗周围神经损伤奠定了实验及理论基础。
第二部分:靶肌肉注射促红细胞生成素对大鼠周围神经再生的作用
目的探讨靶肌肉注射人重组促红细胞生成素(recombinant human erythropoietin ,rh-EPO)对大鼠坐骨神经损伤后神经再生的作用。
方法选用健康雄性SD大鼠12只,制备大鼠右侧坐骨神经钳夹损伤模型。实验动物随机分为2组,每组6只,EPO组:靶肌肉注射rh-EPO 2500U/kg;对照组:注射同体积的生理盐水。术后第7d、14d、21d观察坐骨神经功能指数(SFI),第21d检测右小腿腓肠肌湿重及组织学观察脊髓腰膨大(L4～L6)、夹伤远端坐骨神经、损伤侧腓肠肌组织并作图象分析测定脊髓前角运动神经元数、再生有髓神经纤维数、髓鞘厚度、轴突直径和腓肠肌肌细胞截面积等指标。
结果术后第7d两组SFI无显著性差异,术后第14d、21d EPO组SFI恢复程度明显大于对照组,差别有显著性意义(P<0.05);术后第21d右小腿腓肠肌肌湿重(mg),EPO组为554.27±51.96(mg),与对照组451.67±66.79(mg)比较差异有显著性意义(P<0.05);术后第21d损伤侧脊髓前角运动神经元数、再生有髓神经纤维数、髓鞘厚度、轴突直径和腓肠肌肌细胞截面积等指标,EPO组均优于对照组(P<0.05,P<0.01)。结论靶肌肉注射rh-EPO能促进周围神经再生和功能恢复。
第三部分:外源性促红细胞生成素对失神经肌肉萎缩的影响
目的探讨外源性促红细胞生成素对失神经支配肌肉的影响。
方法SD大鼠24只,在梨状肌下缘切断坐骨神经,制作小腿三头肌失神经支配模型。实验动物随机分为EPO组(n=12)和对照组(n=12), EPO组于术后小腿腓肠肌内注射rh-EPO2500U/kg;对照组小腿腓肠肌内注射等量生理盐水;每天注射一次。于术后第2、4周检测两组肌湿重、肌肉蛋白含量、肌细胞直径和横切面积,肌肉Na~+-K~+-ATP酶和Ca~(2+)-ATP酶活性及骨骼肌细胞凋亡率变化。
结果术后第2、4周EPO组肌湿重、肌肉蛋白含量、肌细胞直径和横切面积,肌肉Na~+-K~+-ATP酶和Ca~(2+)-ATP酶活性均明显高于对照组(P<0.05),而EPO组肌细胞凋亡数明显低于对照组(P<0.05)。
结论外源性EPO具有明显延缓失神经肌肉萎缩的作用。
Part one: Expression of EPO and its receptors in the spinal cord、dorsal root ganglia and sciatic nerve and their changes after injury of rat sciatic nerves
Objective To investigate the expression and the pattern of EPO and its receptors (EPOR) in the spinal cord, the dorsal root ganglia and the sciatic nerve after sciatic nerves crushed injury in rats.
Methods Thirty-six male adult Sprague-Dawley rats were divided randomly into normal group,control group and experimental group. The rats of experimental group were received crushed to bilateral sciatic nerves and L4～L6 spinal cords , dorsal root ganglias and sciatic nerves were harvested respectively at 1d,7d,14d and 28d after operation. Immunohistochemical method and Reverse Transcription-Polymerase Chain Reaction (RT-PCR) for erythropoietin and erythropoietin receptor and image analysis were used to observe the expression of EPO and EPOR.
Results EPO and EPOR were present in uninjured and injured sciatic nerves. They were also expressed in normal dorsal root ganglias. After crush injury, EPO expression is increased and EPOR is decreased.EPO immunostaining and RT-PCR were unoberserved in motor neurons of spinal cord in normal group and experimental group,however, EPOR were noted in motor neurons of spinal cord in normal group and after sciatic nerves crush injury.
Conclusion The results reveal the favorable effects of EPO on nerve regeneration from the angles of central neurons, which establishes the experimental and theoretical foundation in the further treating peripheral nerve injuries with EPO.
Part two: Effect of target muscle injection of recombinant human erythropoietin on peripheral nerve regeneration in rats
Objective To investigate the effect of target muscle injection of recombinant human erythropoietin(rh-EPO)on the nerve regeneration of adult rats sciatic nerves. Methods 12 healthy male Sprague-Dawley rats were involved and right sciatic nerve crushed model was used.The experimental rats were divided randomly into two groups: the EPO group and the control group, 6 rats in each group. Rh-EPO 2500U/kg was injected daily into the gastrocnemius in EPO group , and normal saline was injected into the gastrocnemius every day after operation in control group. At days 7、14 and 21 after operation, the sciatic function index (SFI) was determined by walking tract analysis. At 21 days after operation,the muscle wet weights were measured,and the spinal cord segments (L4～L6 ),the distal site of injured sciatic nerve and the injured gastrocnemius muscle were observed by light microscope.The count of motor neurons of anterior horn , the number of myelinated fibers , the cross section areas of gastrocnemius muscle cells and other parameters were determined.
Results At day 7 after operation , SFI scores had no significant difference between two groups;at day 14 and 21 after operation ,SFI score of EPO group was significantly higher than that of the control group(P<0.01). At day 21 after operation,the gastrocnemius muscle wet weights in the EPO group and the control group were 554.27±51.96(mg) and 451.67±66.79(mg) respectively, with significant difference between the EPO group and the control group(P<0.05). The numbers of motor neurons of anterior horn, myelinated nerve fibers,diameter of axon,thick of myelin sheath and the cross section areas of gastrocnemius muscle cells in EPO group were significantly superior to those in control group(P< 0.05 ,P<0.01).
Conclusion Target muscle injected rh-EPO can promote the injured nerve regeneration and improve the recovery of their function.
Part three: The effect of exogenous erythropoietin on the denervated muscle atrophy Objective To study the effect of exogenous recombinant human EPO (rh-EPO)on the denervated muscular atrophy.
Methods 24 male Sprague-Dawley rats were involved. Model of denervated gastrocnemius muscle was set up after sciatic nerves were transected at the right lower limb. The rats were randomly divided into two groups: the EPO group and the control group. Rh-EPO 2500U/kg was injected daily into the denervated gastrocnemius in EPO group , and normal saline was injected into the denervated gastrocnemius in control group.At 2 and 4 weeks after operation, the muscle wet weight, the muscle cell diameter and cross section areas, the protein amount, the percentage of the apoptotic muscle cells and Na~+-K~+-ATPase and Ca~(2+)-ATPase activities were observed.
Results At 2 and 4 weeks after operation, the muscle wet weight, Na~+-K~+-ATPase and Ca~(2+)-ATPase activities,the muscle cell diameter and cross section areas and the protein amount were significantly greater in EPO group than those in control group, however, the percentage of the apoptotic muscle cells was significantly smaller in EPO group than that in control group .
Conclusions Exogenous erythropoietin can delay the denervated muscle atrophy.
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