丙戊酸对大鼠臂丛神经根性撕脱伤后脊髓运动神经元保护作用及其分子机制研究
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摘要
目的意义
臂丛神经根性撕脱伤是最严重、最难修复的一种周围神经损伤。由于其病情复杂、诊断困难及并发症严重，不仅给患者带来机体和心理的双重残疾，亦给其家庭及社会带来沉重负担。随着显微外科技术的发展，神经吻合、神经移位等手术方法已广泛应用于神经根性撕脱伤的临床治疗，但由于撕脱伤后脊髓运动神经元出现大量死亡，神经再生缺乏“原动力”，导致术后肢体功能的恢复十分困难。丙戊酸作为抗癫痫、情绪稳定剂是神经科疾病治疗的常用药物。新近研究表明，丙戊酸尚可促进体外培养的神经细胞存活及再生，但对于其体内神经保护作用及相关机制，尤其是对臂丛神经根性撕脱伤后运动神经元的保护作用还知之甚少。
本研究通过建立全臂丛神经根性撕脱伤的动物模型，应用Western blot、实时荧光定量PCR、免疫组化、尼氏体染色和TUNEL等检测技术，探讨丙戊酸对臂丛神经根性撕脱伤后运动神经元的保护作用及其分子机制，为丙戊酸早日应用于临床促进周围神经损伤后肢体功能恢复提供理论基础。
材料方法
成年Wistar雄性大鼠288只，随机等分为假手术组（麻醉后显露臂丛神经后直接闭合创口）、单纯损伤组（臂丛神经根性撕脱伤）和丙戊酸组（臂丛神经根性撕脱伤+每日丙戊酸300mg/kg）。三组大鼠分别在伤后1、2、3、7、14和28天固定时间内处死并留取脊髓C5-T1段。尼氏体染色法观察脊髓运动神经元存活数；TUNEL法检测运动神经元凋亡数；透射电镜观察运动神经元及胶质细胞的超微结构；免疫组化法检测c-Jun和Bcl-2在脊髓运动神经元内的表达情况及阳性细胞数；Western blot法和实时定量荧光PCR分别检测c-Jun和Bcl-2的蛋白及mRNA表达水平。
研究结果
1．脊髓存活运动神经元计数：单纯损伤组和丙戊酸组伤后1至7天神经元数量均无明显变化，14天和28天数量急剧减少。两组比较，丙戊酸组神经元存活数量较多，在第14天(p<0.05)和28天(p<0.01)差异具有统计学意义。
2．脊髓运动神经元凋亡细胞计数：单纯损伤组和丙戊酸组伤后第1天无阳性表达，第2至28天均可见凋亡细胞。两组比较，丙戊酸组神经元凋亡数量明显减少，在第3天(p<0.01)和7天(p<0.01)差异具有统计学意义。
3．脊髓运动神经元及胶质细胞超微结构观察：单纯损伤组和丙戊酸组伤后均可见神经毡内部分空化，轴突溶解。单纯损伤组运动神经元可见核切迹、核固缩等细胞损伤和死亡现象；而丙戊酸组胞质内可见粗面内质网和线粒体增多。单纯损伤组神经胶质细胞可见核肥大、边聚，部分细胞空化坏死；而丙戊酸组的胞质内可见大量粗面内质网及核糖体，细胞空化不明显。
4．脊髓运动神经元c-Jun蛋白表达变化：①c-Jun蛋白主要分布于运动神经元细胞核内。②单纯损伤组和丙戊酸组伤后c-Jun表达的阳性神经元百分比和蛋白量明显增高：c-Jun蛋白于第1天反应性升高，第3天达峰值，之后逐渐降低。两组比较，丙戊酸组c-Jun表达的阳性细胞数较少，伤后第1天(p<0.05)、2天(p<0.01)、3天(p<0.05)、7天(p<0.05)差异具有统计学意义；丙戊酸组c-Jun蛋白表达量减少，伤后第1天(p<0.05)、2天(p<0.05)、3天(p<0.01)、7天(p<0.05)差异具有统计学意义。③单纯损伤组和丙戊酸组伤后c-Jun mRNA表达均上调，于第1天反应性升高，第3天达峰值。两组比较，丙戊酸组表达水平较低，伤后第1天(p<0.05)、2天(p<0.05)、3天(p<0.01)、7天(p<0.05)有统计学差异。
5．脊髓运动神经元Bcl-2蛋白表达变化：①Bcl-2蛋白主要分布于运动神经元细胞浆内；②单纯损伤组和丙戊酸组伤后Bcl-2表达的阳性神经元百分比和蛋白量亦明显升高：Bcl-2蛋白于第1天升高，第7天达峰值，后逐渐回落。两组比较，丙戊酸组Bcl-2表达的阳性细胞数较多，伤后第1天(p<0.05)、2天(p<0.01)、3天(p<0.01)、7天(p<0.01)和14天(p<0.05)差异具有统计学意义；丙戊酸组Bcl-2蛋白表达量增多，伤后第2天(p<0.01)、3天(p<0.05)、7天(p<0.05)差异具有统计学意义。③单纯损伤组和丙戊酸组伤后Bcl-2蛋白的mRNA表达均上调，于第1天反应性升高，第7天达峰值。两组比较，丙戊酸组表达水平明显增高，伤后第2天(p<0.05)、3天(p<0.05)、7天(p<0.05)具有统计学差异。
研究结论
1．改良全臂丛神经根性撕脱伤动物模型的神经根性撕脱确切、副损伤小、模型稳定、符合创伤实际机制；
2．全臂丛神经根性撕脱伤可导致脊髓相应节段内运动神经元大量死亡，应用丙戊酸可减少神经元凋亡、增加神经元存活数量，发挥其保护神经的作用；
3．全臂丛神经根性撕脱伤后可引起脊髓相应节段运动神经元c-Jun蛋白与Bcl-2蛋白表达上调，而应用丙戊酸则可抑制神经元的c-Jun蛋白表达、增加Bcl-2蛋白表达。丙戊酸通过下调c-Jun蛋白、上调Bcl-2蛋白表达抑制神经细胞凋亡、增加细胞存活数量，可能是其神经保护作用的重要机制之一。
Objectives:
Brachial plexus root avulsion is a severe peripheral nerve injury that causes physical andpsychological disability. At present, with advanced microsurgery techniques, nerveanastomosis, nerve grafting and so on are available surgical options for treating this devastatinginjury. However, death of a major neuronal pool and complex interventions are usuallyassociated with poor results. Valproic acid (VPA), an anticonvulsant and mood-stabilizing drug,has been found exerting neuroprotection. It has been reported to enhance neurite outgrowth andto protect neurons from death in vitro. But the potential neuroprotective actions of VPA,especially its neuroprotection of the spinal cord following brachial plexus root avulsion, havenot yet well studied. After brachial plexus root avulsion, we harvest spinal cord (C5-T1) forWestern-blot, immunohistochemistry, real-time quantitative PCR, Nissl staining and TUNELanalysis to study the neuroprotection role of valproic against the brachial plexus root avulsioninduced motoneurons death. We hope the results can serve as a theoretical underpinning for thetreatment of brachial plexus root avulsion with VPA.
Methods:
Two hundred and eighty eight Wistar rats were randomly divided into three groups: shamoperation, control group (rats have brachial plexus root avulsion), VPA treated group (rats havebrachial plexus root avulsion and were orally administrated daily with VPA dissolved indrinking water at300mg/kg). The rats were sacrificed at day1,2,3,7,14and28after surgeryfor harvesting C5-T1tissue samples. We used Nissl staining and TUNEL to analyze thepercentage of surviving motoneurons and apoptotic cells, and transmission electron microscopewas used to observe the ultrastructure in motoneurons and gliacytes. We usedimmunohistochemistry to observe distribution rule of c-Jun and Bcl-2in neuron, real-timequantitative PCR and Western blot to measure the mRNA and protein quantity of c-Jun andBcl-2.
Results:
1. Dramatic decrease of motoneurons in the spinal cord was resulted by brachial plexus rootavulsion, the percentage of surviving motoneurons was significantly increased at day14(p<0.05) and28(p<0.01).
2. At day1after avulsion, no TUNEL stained motoneurons were observed. TUNEL positive(apoptotic) motoneurons appeared at day2, followed by a gradual change until day28. Thepercentage of apoptotic motoneurons in VPA group was significantly decreased at day3(p<0.01) and7(p<0.01) as compared to control group.
3. Ultrathin sections were cut and collected on copper grids for counterstaining with uranylacetate and lead citrate. The cavitates were formed and organelles were disappeared in thecytoplasm or nuclear matrix of motoneurons on the injured side of control group after avulsion.In VPA group, however, a number of mitochondria, rough endoplasmic reticulums, andribosomes, as well as a regular contour of the nuclear membrane were observable. Afteravulsion, the cytoplasm and nuclei in abnormal gliacytes on the injured side of control groupwas electron dense with a hypertrophied and sub-marginalized nucleolus. In contrast, thecytoplasm and nuclei of gliacytes on the injured side of VPA group had a normal appearancewith more rough endoplasmic reticulum and ribosome.
4. c-Jun expressing in motoneurons:(1) c-Jun expressed in the nucleus.(2) Compared withsham operation, the percentage of c-Jun positive motoneurons was increased. At day1(p<0.05), day2(p<0.01), day3(p<0.05), and day7(p<0.05) after avulsion, the percentage ofc-Jun positive motoneurons in VPA group was relatively less than that in control group. thequantity of c-Jun in control group was increased from day1, with a peak at day3, and thendescended sharply at day14after which the values had a plateau. The quantity of c-Jun proteinwas significantly decreased in VPA group than in control group at day1(p<0.05), day2(p<0.05), day3(p<0.01) and day7(p<0.05).(3) Compated with sham operation, the quantityof c-Jun mRNA in control group was increased from day1, with peak at day3, and thendescended sharply at day14, after which the values had a plateau. the quantity of c-JunmRNA was significantly decreased in VPA group than in control group at day1(p<0.05), day2(p<0.05), day3(p<0.01) and day7(p<0.05).
5. Bcl-2expressing in motoneurons:(1) Bcl-2expressed in the cytoplasm of motoneurons. (2) Compared with sham operation, the percentage of c-Jun and Bcl-2positive motoneuronswas increased. The percentage of Bcl-2positive motoneurons was significantly larger in VPAgroup than in control group at each time point except at day28(day1p<0.05, day2p<0.01,day3p<0.01, day7p<0.01, day14p<0.05). The quantity of Bcl-2in VPA group was increasedfrom day1, with a peak at day7, and then descended sharply at day14, after which the valuesalso had a plateau. The quantity of Bcl-2protein was significantly increased in VPA group thanin control group at day2(p<0.01), day3(p<0.05) and day7(p<0.05).(3) Compated withsham operation, the quantity of Bcl-2mRNA in VPA group was increased from day1to day3with peak at day7, and then descended sharply at day14, after which the values also had aplateau. The quantity of Bcl-2mRNA was significantly increased in VPA group than in controlgroup at day2(p<0.05), day3(p<0.05) and day7(p<0.05).
Conclusions:
1. The improved animal model of brachial plexus root avulsion has fewer side effects, andhas the same mechanism of avulsion in practice.
2. The results showed that brachial plexus root avulsion induced dramatic death ofmotoneuronts, and with VPA administration, the survival of motoneurons was promoted andthe cell apoptosis was inhibited.
3. The present study reported that brachial plexus root avulsion decreasing c-Jun expressionand increasing Bcl-2expression. Motoneurons were protected by VPA against brachial plexusroot avulsion induced death through both decreasing c-Jun expression and increasing Bcl-2expression directly or indirectly.
臂丛神经根性撕脱伤是最严重、最难修复的一种周围神经损伤。由于其病情复杂、诊断困难及并发症严重，不仅给患者带来机体和心理的双重残疾，亦给其家庭及社会带来沉重负担。随着显微外科技术的发展，神经吻合、神经移位等手术方法已广泛应用于神经根性撕脱伤的临床治疗，但由于撕脱伤后脊髓运动神经元出现大量死亡，神经再生缺乏“原动力”，导致术后肢体功能的恢复十分困难。丙戊酸作为抗癫痫、情绪稳定剂是神经科疾病治疗的常用药物。新近研究表明，丙戊酸尚可促进体外培养的神经细胞存活及再生，但对于其体内神经保护作用及相关机制，尤其是对臂丛神经根性撕脱伤后运动神经元的保护作用还知之甚少。
本研究通过建立全臂丛神经根性撕脱伤的动物模型，应用Western blot、实时荧光定量PCR、免疫组化、尼氏体染色和TUNEL等检测技术，探讨丙戊酸对臂丛神经根性撕脱伤后运动神经元的保护作用及其分子机制，为丙戊酸早日应用于临床促进周围神经损伤后肢体功能恢复提供理论基础。
材料方法
成年Wistar雄性大鼠288只，随机等分为假手术组（麻醉后显露臂丛神经后直接闭合创口）、单纯损伤组（臂丛神经根性撕脱伤）和丙戊酸组（臂丛神经根性撕脱伤+每日丙戊酸300mg/kg）。三组大鼠分别在伤后1、2、3、7、14和28天固定时间内处死并留取脊髓C5-T1段。尼氏体染色法观察脊髓运动神经元存活数；TUNEL法检测运动神经元凋亡数；透射电镜观察运动神经元及胶质细胞的超微结构；免疫组化法检测c-Jun和Bcl-2在脊髓运动神经元内的表达情况及阳性细胞数；Western blot法和实时定量荧光PCR分别检测c-Jun和Bcl-2的蛋白及mRNA表达水平。
研究结果
1．脊髓存活运动神经元计数：单纯损伤组和丙戊酸组伤后1至7天神经元数量均无明显变化，14天和28天数量急剧减少。两组比较，丙戊酸组神经元存活数量较多，在第14天(p<0.05)和28天(p<0.01)差异具有统计学意义。
2．脊髓运动神经元凋亡细胞计数：单纯损伤组和丙戊酸组伤后第1天无阳性表达，第2至28天均可见凋亡细胞。两组比较，丙戊酸组神经元凋亡数量明显减少，在第3天(p<0.01)和7天(p<0.01)差异具有统计学意义。
3．脊髓运动神经元及胶质细胞超微结构观察：单纯损伤组和丙戊酸组伤后均可见神经毡内部分空化，轴突溶解。单纯损伤组运动神经元可见核切迹、核固缩等细胞损伤和死亡现象；而丙戊酸组胞质内可见粗面内质网和线粒体增多。单纯损伤组神经胶质细胞可见核肥大、边聚，部分细胞空化坏死；而丙戊酸组的胞质内可见大量粗面内质网及核糖体，细胞空化不明显。
4．脊髓运动神经元c-Jun蛋白表达变化：①c-Jun蛋白主要分布于运动神经元细胞核内。②单纯损伤组和丙戊酸组伤后c-Jun表达的阳性神经元百分比和蛋白量明显增高：c-Jun蛋白于第1天反应性升高，第3天达峰值，之后逐渐降低。两组比较，丙戊酸组c-Jun表达的阳性细胞数较少，伤后第1天(p<0.05)、2天(p<0.01)、3天(p<0.05)、7天(p<0.05)差异具有统计学意义；丙戊酸组c-Jun蛋白表达量减少，伤后第1天(p<0.05)、2天(p<0.05)、3天(p<0.01)、7天(p<0.05)差异具有统计学意义。③单纯损伤组和丙戊酸组伤后c-Jun mRNA表达均上调，于第1天反应性升高，第3天达峰值。两组比较，丙戊酸组表达水平较低，伤后第1天(p<0.05)、2天(p<0.05)、3天(p<0.01)、7天(p<0.05)有统计学差异。
5．脊髓运动神经元Bcl-2蛋白表达变化：①Bcl-2蛋白主要分布于运动神经元细胞浆内；②单纯损伤组和丙戊酸组伤后Bcl-2表达的阳性神经元百分比和蛋白量亦明显升高：Bcl-2蛋白于第1天升高，第7天达峰值，后逐渐回落。两组比较，丙戊酸组Bcl-2表达的阳性细胞数较多，伤后第1天(p<0.05)、2天(p<0.01)、3天(p<0.01)、7天(p<0.01)和14天(p<0.05)差异具有统计学意义；丙戊酸组Bcl-2蛋白表达量增多，伤后第2天(p<0.01)、3天(p<0.05)、7天(p<0.05)差异具有统计学意义。③单纯损伤组和丙戊酸组伤后Bcl-2蛋白的mRNA表达均上调，于第1天反应性升高，第7天达峰值。两组比较，丙戊酸组表达水平明显增高，伤后第2天(p<0.05)、3天(p<0.05)、7天(p<0.05)具有统计学差异。
研究结论
1．改良全臂丛神经根性撕脱伤动物模型的神经根性撕脱确切、副损伤小、模型稳定、符合创伤实际机制；
2．全臂丛神经根性撕脱伤可导致脊髓相应节段内运动神经元大量死亡，应用丙戊酸可减少神经元凋亡、增加神经元存活数量，发挥其保护神经的作用；
3．全臂丛神经根性撕脱伤后可引起脊髓相应节段运动神经元c-Jun蛋白与Bcl-2蛋白表达上调，而应用丙戊酸则可抑制神经元的c-Jun蛋白表达、增加Bcl-2蛋白表达。丙戊酸通过下调c-Jun蛋白、上调Bcl-2蛋白表达抑制神经细胞凋亡、增加细胞存活数量，可能是其神经保护作用的重要机制之一。
Objectives:
Brachial plexus root avulsion is a severe peripheral nerve injury that causes physical andpsychological disability. At present, with advanced microsurgery techniques, nerveanastomosis, nerve grafting and so on are available surgical options for treating this devastatinginjury. However, death of a major neuronal pool and complex interventions are usuallyassociated with poor results. Valproic acid (VPA), an anticonvulsant and mood-stabilizing drug,has been found exerting neuroprotection. It has been reported to enhance neurite outgrowth andto protect neurons from death in vitro. But the potential neuroprotective actions of VPA,especially its neuroprotection of the spinal cord following brachial plexus root avulsion, havenot yet well studied. After brachial plexus root avulsion, we harvest spinal cord (C5-T1) forWestern-blot, immunohistochemistry, real-time quantitative PCR, Nissl staining and TUNELanalysis to study the neuroprotection role of valproic against the brachial plexus root avulsioninduced motoneurons death. We hope the results can serve as a theoretical underpinning for thetreatment of brachial plexus root avulsion with VPA.
Methods:
Two hundred and eighty eight Wistar rats were randomly divided into three groups: shamoperation, control group (rats have brachial plexus root avulsion), VPA treated group (rats havebrachial plexus root avulsion and were orally administrated daily with VPA dissolved indrinking water at300mg/kg). The rats were sacrificed at day1,2,3,7,14and28after surgeryfor harvesting C5-T1tissue samples. We used Nissl staining and TUNEL to analyze thepercentage of surviving motoneurons and apoptotic cells, and transmission electron microscopewas used to observe the ultrastructure in motoneurons and gliacytes. We usedimmunohistochemistry to observe distribution rule of c-Jun and Bcl-2in neuron, real-timequantitative PCR and Western blot to measure the mRNA and protein quantity of c-Jun andBcl-2.
Results:
1. Dramatic decrease of motoneurons in the spinal cord was resulted by brachial plexus rootavulsion, the percentage of surviving motoneurons was significantly increased at day14(p<0.05) and28(p<0.01).
2. At day1after avulsion, no TUNEL stained motoneurons were observed. TUNEL positive(apoptotic) motoneurons appeared at day2, followed by a gradual change until day28. Thepercentage of apoptotic motoneurons in VPA group was significantly decreased at day3(p<0.01) and7(p<0.01) as compared to control group.
3. Ultrathin sections were cut and collected on copper grids for counterstaining with uranylacetate and lead citrate. The cavitates were formed and organelles were disappeared in thecytoplasm or nuclear matrix of motoneurons on the injured side of control group after avulsion.In VPA group, however, a number of mitochondria, rough endoplasmic reticulums, andribosomes, as well as a regular contour of the nuclear membrane were observable. Afteravulsion, the cytoplasm and nuclei in abnormal gliacytes on the injured side of control groupwas electron dense with a hypertrophied and sub-marginalized nucleolus. In contrast, thecytoplasm and nuclei of gliacytes on the injured side of VPA group had a normal appearancewith more rough endoplasmic reticulum and ribosome.
4. c-Jun expressing in motoneurons:(1) c-Jun expressed in the nucleus.(2) Compared withsham operation, the percentage of c-Jun positive motoneurons was increased. At day1(p<0.05), day2(p<0.01), day3(p<0.05), and day7(p<0.05) after avulsion, the percentage ofc-Jun positive motoneurons in VPA group was relatively less than that in control group. thequantity of c-Jun in control group was increased from day1, with a peak at day3, and thendescended sharply at day14after which the values had a plateau. The quantity of c-Jun proteinwas significantly decreased in VPA group than in control group at day1(p<0.05), day2(p<0.05), day3(p<0.01) and day7(p<0.05).(3) Compated with sham operation, the quantityof c-Jun mRNA in control group was increased from day1, with peak at day3, and thendescended sharply at day14, after which the values had a plateau. the quantity of c-JunmRNA was significantly decreased in VPA group than in control group at day1(p<0.05), day2(p<0.05), day3(p<0.01) and day7(p<0.05).
5. Bcl-2expressing in motoneurons:(1) Bcl-2expressed in the cytoplasm of motoneurons. (2) Compared with sham operation, the percentage of c-Jun and Bcl-2positive motoneuronswas increased. The percentage of Bcl-2positive motoneurons was significantly larger in VPAgroup than in control group at each time point except at day28(day1p<0.05, day2p<0.01,day3p<0.01, day7p<0.01, day14p<0.05). The quantity of Bcl-2in VPA group was increasedfrom day1, with a peak at day7, and then descended sharply at day14, after which the valuesalso had a plateau. The quantity of Bcl-2protein was significantly increased in VPA group thanin control group at day2(p<0.01), day3(p<0.05) and day7(p<0.05).(3) Compated withsham operation, the quantity of Bcl-2mRNA in VPA group was increased from day1to day3with peak at day7, and then descended sharply at day14, after which the values also had aplateau. The quantity of Bcl-2mRNA was significantly increased in VPA group than in controlgroup at day2(p<0.05), day3(p<0.05) and day7(p<0.05).
Conclusions:
1. The improved animal model of brachial plexus root avulsion has fewer side effects, andhas the same mechanism of avulsion in practice.
2. The results showed that brachial plexus root avulsion induced dramatic death ofmotoneuronts, and with VPA administration, the survival of motoneurons was promoted andthe cell apoptosis was inhibited.
3. The present study reported that brachial plexus root avulsion decreasing c-Jun expressionand increasing Bcl-2expression. Motoneurons were protected by VPA against brachial plexusroot avulsion induced death through both decreasing c-Jun expression and increasing Bcl-2expression directly or indirectly.
引文
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