SD大鼠脊髓全横断后运动神经元中NT-3和TrkC的表达变化
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摘要
背景：
脊髓损伤是一严重创伤,常规的治疗效果不佳,使相当一部分病人遗留运动、感觉、膀胱及直肠功能障碍。神经营养因子是神经损伤修复与功能重建的必要物质基础,从内源性神经营养因子3(NT-3)及其受体TrkC表达的相关分子机制及脊髓可塑性入手,探索促进脊髓损伤修复的新策略是当前国际神经科学界研究的重要内容之一。
目的：
研究成年SD大鼠脊髓全横断后损伤位点头尾侧及其相联系的阳性运动神经元中NT-3及其受体TrkC表达的时相变化,探讨内源性NT-3及TrkC在脊髓损伤修复中的内源性作用机制及其与脊髓可塑性的关系。
方法：
取健康成年SD大鼠(200-220克)42只,随机分成6组：每组7只,其中一组为假手术对照组,余为脊髓全横断模型组。模型动物分别于手术后1天、3天、7天、14天、28天,取损伤节段上、下各1cm的脊髓4段(大约为T8-T11脊髓节段)和双侧大脑运动皮层、中脑红核节段,共7处组织标本。其中,各组中3只用于免疫组化染色以了解NT-3及TrkC的原位分布,2只用于Western Blot检测NT-3及TrkC的蛋白含量,2只用于RT-PCR检测NT-3及TrkC的基因表达水平。各组大鼠在存活期间均行后肢BBB运动功能评分。用于免疫组化的大鼠水合氯醛腹腔注射麻醉后,4%多聚甲醛经升主动脉灌注后取材,组织后固定、入20%、25%、30%蔗糖溶液梯度脱水沉底后制作20μm连续冰冻切片,以NT-3及TrkC抗体行免疫组化SP三步法DAB染色和荧光染色并作对照。光镜和荧光显微镜下观察免疫阳性反应物的正常原位分布情况,观测并计数假手术和脊髓全横断损伤后,成年SD大鼠脊髓腹角和大脑皮质前运动区NT-3及TrkC阳性神经元的形态学变化、分布及亚细胞定位。用于western blot和RT-PCR检测的大鼠麻醉后,于活体下快速取材,部位同上,冲洗后冰浴下匀浆,将提取的蛋白离心、分装。用于RT-PCR检测的活取组织加入TRIzol作RNA抽提。电泳及免疫印迹检测后,利用凝胶成像系统分析各杂交带的光密度值及灰度值的时空变化。结果采用SPSS13.0统计软件包进行单因素方差分析、LSD检验等统计学处理。
结果：
1.Western blotting特异性的识别分子量13.6Kda和145Kda处的条带对应NT-3和TrkC的分子量,置换试验、阴性对照试验均为阴性。
2.免疫组化技术观察结果：(1)运用免疫组化技术,观察到不同强度的NT-3和TrkC免疫阳性产物广泛分布于大鼠的运动神经元、中间神经元和胶质细胞。(2)通过Western blotting半定量,显示NT-3在大鼠脑干、海马区含量较丰富。
3.假手术组和手术各组均观察到NT-3和TrkC阳性神经元,NT-3定位于胞浆和胞核,胞核染色非常明显,强于胞浆和神经纤维；TrkC主要定位于阳性细胞的胞浆,假手术组极少见于神经树突或神经末梢,未见于大脑运动皮层表达。脊髓损伤后,TrkC的阳性核染明显强化,强染色也见于一些树状分支和轴突,仍未见于大脑中央运动皮层表达。
4.脊髓损伤模型大鼠NT-3和TrkC的表达变化：(1)脊髓全横断损伤处上、下节段各组大鼠前角NT-3免疫阳性神经元平均数目比较均有显著差异(P<0.001)；各手术组前角NT-3免疫阳性神经元平均数目均显著低于假手术对照组(P<0.05)；由多重比较结果及图38可以看出,手术1d组较对照组神经元平均数目显著下降,随后呈逐渐上升趋势,一直到术后28d,仍保持较高增长趋势。各组SD大鼠脊髓全横断损伤处上节段前角NT-3免疫阳性神经元与下节段前角NT-3免疫阳性神经元比较均无显著差异(P=0.184-1.000)。(2)脊髓全横断损伤后,1d至7d的TrkC表达在损伤部位(T10、T11)和相邻节段(T9、T12)对比假手术组表现下调,在14d、28d表现为恢复至假手术组水平；TrkC的表达水平头侧明显高于尾侧；损伤节段又明显高于相邻节段。Western blotting半定量检测未能观察到TrkC蛋白在大脑运动皮层表达。(3)脊髓损伤后TrkC的mRNA水平临时变化模式与TrkC蛋白水平变化相似,1d至7d表现对比假手术组有明显的减少,14d恢复至略高于假手术组的水平,对比假手术组在不同时点大脑运动皮层的表达均维持在一个相对低的水平。(4)NT-3和TrkC在脊髓灰质的灰度值测试大致与免疫组化的变化趋势相一致。
5.大脑皮质运动区NT-3阳性神经元的变化趋势同脊髓前角运动神经元的变化趋势一致。
6.BBB运动功能评分：对照组为21分,1d、3d时呈完全性瘫痪状态(0),从7d(0.57)起逐步恢复,28d时最高(2.57)。
结论：
1.通过对抗体的鉴定,证实本实验采用的兔抗NT-3多克隆抗体和鼠抗TrkC单克隆抗体是高度特异性抗体。
2.NT-3和TrkC在成年SD大鼠的运动神经元均有表达,而NT-3和TrkC在大鼠中枢神经系统的表达既有重叠又存在差异,提示这一对配体和受体均可能参与了大鼠脑和脊髓神经细胞的生理功能,但在不同区域的它们各自发挥着不同的作用。
3.NT-3和TrkC在脊髓全横断损伤后均有表达,其时相变化有一定差异,表明这一对配体和受体的表达与脊髓损伤修复过程有关,但在损伤的不同时段和它们的作用方式可能存在一定差异,这为临床运用NTFs治疗脊髓损伤提供一定的实验依据。
Bachground:
Spinal injury is a serve trauma. For the reason of its conventional therapeutic efficacy not well, a lot of patients remained sequela such as dyskinesia, sensory disability, dysfunction of bladder and rectum. Neurotrophic factor is essential material for nerve injury recovery and functional reconstruction.To begin with correlated molecule mechanism of endogenous NT-3 and its receptor TrkC expression,,exploring new strategy to promote spinal injury recovery is one of significance content about international neuroscience researching area.
Objective:
To investigate the phase changes of NT-3 and TrkC from relative motor neurons in injury segment bilateralis of adult Sprague-Dawley rats subjected to cord transection by both immunohistochemistry, Western blotting and RT-PCR, and also give primary discussion about the temporal changes and endogenous action mechanisms of endogenous NT-3 and TrkC following transected spinal cord injury,and make understanding its relationship with plasticity of spinal cord.
Method:
Adult female Sprague-Dawley rats (200g-220g) were used in our study. Adult SD rats were divided into six groups randomly with seven rats each group.One group is sham operation and the other groups for spinal cord transaction. Spinal cord transection were performed at T9 to T10 level in rats from five groups, while control group did not receive transection of the spinal cord. The rats received spinal cord transection were allowed to survive for 1 days,3 days,7 days,14days and 28days.While the time point reach,experimental rats were sacrificed. Seven tissue sample were removed such as two sides cerebral cortex, midbrain,4 columns from caudal and rostral ambi-1 cm spinal cord around the injury site corresponding T8 to T11 level. After perfusion, Samples from 3 rats each group were processed for NT-3 and TrkC immunohistochemistry. And then, fresh sample from 2 rats each group were obtained for the use of sem-qualification by western blotting and qualification by RT-PCR. Hindlimb function was evaluated and recorded after operation. Through postfix and dehydration,The sample for immunohistochemistry was cut to 20μm thick frozen sections. By the irnrnunohistochemical SP and fluorescence staining method, we observed the morphology,distribution and subcellular localization of NT-3 and TrkC immununoreactive cells in the ventral horn of the spinal cord and the motor area of the cerebrum. The immunoreactive cells were counted and the Optical densities (OD) were measured. The protein of NT-3 and TrkC was measured by western blotting method for sem-qualification. The mRNA of NT-3 and TrkC was measured by RT-PCR for qualification.The data were statistically anaiysed with one-way ANOVA and LSD test using SPSS 13.0 statistical package.
Result:
1. Western blotting strap specificity recogniting molecular mass 13.6Kda and 145Kda corresponded molecular mass of NT-3 and TrkC respectively. Replace experiment and negative control experiment is negative.
2.According to the irnrnunohistochemical outcome, Varying intensities of NT-3 and TrkC immnuostaining were observed in a wide variety of motor neurons, endaxoneuron and glial cells in the rat central nervous system. Through sem-qualification by western blotting, The most high concentration of NT-3 was detected in brainstem and hippocampus of rat brains.
3. The dense NT-3 and TrkC positive products can be observed in the cytoplasm and processes of neurons in sham group and experimental groups.The nuclei and cytoplasm were labeled by NT-3 antibodies.Robust labeling of NT-3 were detected in nuclei. The dense TrkC positive products can be observed in the cytoplasm of neurons, but very few in the processes and nerve terminal, not be observed in the motor cortex.After spinal cord injury, the nuclei stain intensificated obviously and also been observed in some arborescence branch and neurite,but not be observed in centre motor cortex of brain.
4. (1)The means of NT-3 positive neurons from caudal and rostral spinal cord around the injury site have significant deviation (P<0.001). The means of NT-3 positive neurons from cornu anterius medullae spinalis in each experimental group have significant deviation versus sham group (P<0.05). Positive neurons with NT-3 were sharply decreased in 1ST day after SCI. After 1ST day, the number of the NT-3 positive neurons were constantly increasing, at the end of 28th,maintaining the increase tendency. The means of NT-3 positive neurons from caudal and rostral spinal cord around the injury site in each group have no significant deviation (P=0.184-1.000). (2) The means of TrkC positive neurons from caudal and rostral spinal cord around the injury site have shown down regulation versus sham group in 1ST day and 7ST day after SCI, and then,have recovered to the level of sham group in 14ST day and 28ST day after SCI.The expression level of TrkC from rostral was higher than caudal significantly. The expression level of TrkC from injury segment was higher than consecutive segment significantly. Sem-qualification by western blotting can not detected TrkC protein in motor cortex of brain. (3)Resembling to the changes of TrkC protein, mRNA level of TrkC was decreased significantly from 1ST day to 7ST day after SCI versus sham group, but recovered to super-level of sham group in 14ST day.Contrasting sham group, The expression of TrkC mRNA remained a lower level in motor cortex of brain at different time point. (4) The OD of NT-3 and TrkC in cornu anterius medullae spinalis had been a similar tendency with the changes of irnrnunohistochemistry after SCI.
5.Immunoreactivities of NT-3 positive neurons in the fore motor area of cerebral cortex had been a similar tendency with the changes of the motoneurons in the ventral horn after SCI.
6. The BBB score of the sham-operated and normal rats were 21, after spinal cord transection, the rats showed complete paralysis (0), however, spontaneous functional recovery of the rats'hindlimbs occurred during the time-course, and peaked at 28d (2.57).
Conclusion:
1. Our antibodies identification experiments showed that the antisera were specific for the appropriate neurotrophin and did not cross react with other neurotrophins.
2. NT-3 and TrkC were distributed in motor neurons in limited regions of adult brains of rats. NT-3 likewise its receptor TrkC, in majority of regions of rodents brains and ventral horn, having the overlapping expression, but differences also exits,and so did the expression of TrkC. All above indicated NT-3 and TrkC participate the physiological function of nerve cells in the brain and spinal cord of rodents, nevertheless, they performed different action respectively in different region.
3. The temporal changes differences between the positive neurons with NT-3 and that with TrkC after SCI, indicating the expression of NT-3 and TrkC have the relation to the recovery after SCI. However, some discrepancies also can be observed for their mode of action in different time course after SCI. It can offer some theory based on experiment for clinic using NTFs to cure spinal cord injury.
脊髓损伤是一严重创伤,常规的治疗效果不佳,使相当一部分病人遗留运动、感觉、膀胱及直肠功能障碍。神经营养因子是神经损伤修复与功能重建的必要物质基础,从内源性神经营养因子3(NT-3)及其受体TrkC表达的相关分子机制及脊髓可塑性入手,探索促进脊髓损伤修复的新策略是当前国际神经科学界研究的重要内容之一。
目的：
研究成年SD大鼠脊髓全横断后损伤位点头尾侧及其相联系的阳性运动神经元中NT-3及其受体TrkC表达的时相变化,探讨内源性NT-3及TrkC在脊髓损伤修复中的内源性作用机制及其与脊髓可塑性的关系。
方法：
取健康成年SD大鼠(200-220克)42只,随机分成6组：每组7只,其中一组为假手术对照组,余为脊髓全横断模型组。模型动物分别于手术后1天、3天、7天、14天、28天,取损伤节段上、下各1cm的脊髓4段(大约为T8-T11脊髓节段)和双侧大脑运动皮层、中脑红核节段,共7处组织标本。其中,各组中3只用于免疫组化染色以了解NT-3及TrkC的原位分布,2只用于Western Blot检测NT-3及TrkC的蛋白含量,2只用于RT-PCR检测NT-3及TrkC的基因表达水平。各组大鼠在存活期间均行后肢BBB运动功能评分。用于免疫组化的大鼠水合氯醛腹腔注射麻醉后,4%多聚甲醛经升主动脉灌注后取材,组织后固定、入20%、25%、30%蔗糖溶液梯度脱水沉底后制作20μm连续冰冻切片,以NT-3及TrkC抗体行免疫组化SP三步法DAB染色和荧光染色并作对照。光镜和荧光显微镜下观察免疫阳性反应物的正常原位分布情况,观测并计数假手术和脊髓全横断损伤后,成年SD大鼠脊髓腹角和大脑皮质前运动区NT-3及TrkC阳性神经元的形态学变化、分布及亚细胞定位。用于western blot和RT-PCR检测的大鼠麻醉后,于活体下快速取材,部位同上,冲洗后冰浴下匀浆,将提取的蛋白离心、分装。用于RT-PCR检测的活取组织加入TRIzol作RNA抽提。电泳及免疫印迹检测后,利用凝胶成像系统分析各杂交带的光密度值及灰度值的时空变化。结果采用SPSS13.0统计软件包进行单因素方差分析、LSD检验等统计学处理。
结果：
1.Western blotting特异性的识别分子量13.6Kda和145Kda处的条带对应NT-3和TrkC的分子量,置换试验、阴性对照试验均为阴性。
2.免疫组化技术观察结果：(1)运用免疫组化技术,观察到不同强度的NT-3和TrkC免疫阳性产物广泛分布于大鼠的运动神经元、中间神经元和胶质细胞。(2)通过Western blotting半定量,显示NT-3在大鼠脑干、海马区含量较丰富。
3.假手术组和手术各组均观察到NT-3和TrkC阳性神经元,NT-3定位于胞浆和胞核,胞核染色非常明显,强于胞浆和神经纤维；TrkC主要定位于阳性细胞的胞浆,假手术组极少见于神经树突或神经末梢,未见于大脑运动皮层表达。脊髓损伤后,TrkC的阳性核染明显强化,强染色也见于一些树状分支和轴突,仍未见于大脑中央运动皮层表达。
4.脊髓损伤模型大鼠NT-3和TrkC的表达变化：(1)脊髓全横断损伤处上、下节段各组大鼠前角NT-3免疫阳性神经元平均数目比较均有显著差异(P<0.001)；各手术组前角NT-3免疫阳性神经元平均数目均显著低于假手术对照组(P<0.05)；由多重比较结果及图38可以看出,手术1d组较对照组神经元平均数目显著下降,随后呈逐渐上升趋势,一直到术后28d,仍保持较高增长趋势。各组SD大鼠脊髓全横断损伤处上节段前角NT-3免疫阳性神经元与下节段前角NT-3免疫阳性神经元比较均无显著差异(P=0.184-1.000)。(2)脊髓全横断损伤后,1d至7d的TrkC表达在损伤部位(T10、T11)和相邻节段(T9、T12)对比假手术组表现下调,在14d、28d表现为恢复至假手术组水平；TrkC的表达水平头侧明显高于尾侧；损伤节段又明显高于相邻节段。Western blotting半定量检测未能观察到TrkC蛋白在大脑运动皮层表达。(3)脊髓损伤后TrkC的mRNA水平临时变化模式与TrkC蛋白水平变化相似,1d至7d表现对比假手术组有明显的减少,14d恢复至略高于假手术组的水平,对比假手术组在不同时点大脑运动皮层的表达均维持在一个相对低的水平。(4)NT-3和TrkC在脊髓灰质的灰度值测试大致与免疫组化的变化趋势相一致。
5.大脑皮质运动区NT-3阳性神经元的变化趋势同脊髓前角运动神经元的变化趋势一致。
6.BBB运动功能评分：对照组为21分,1d、3d时呈完全性瘫痪状态(0),从7d(0.57)起逐步恢复,28d时最高(2.57)。
结论：
1.通过对抗体的鉴定,证实本实验采用的兔抗NT-3多克隆抗体和鼠抗TrkC单克隆抗体是高度特异性抗体。
2.NT-3和TrkC在成年SD大鼠的运动神经元均有表达,而NT-3和TrkC在大鼠中枢神经系统的表达既有重叠又存在差异,提示这一对配体和受体均可能参与了大鼠脑和脊髓神经细胞的生理功能,但在不同区域的它们各自发挥着不同的作用。
3.NT-3和TrkC在脊髓全横断损伤后均有表达,其时相变化有一定差异,表明这一对配体和受体的表达与脊髓损伤修复过程有关,但在损伤的不同时段和它们的作用方式可能存在一定差异,这为临床运用NTFs治疗脊髓损伤提供一定的实验依据。
Bachground:
Spinal injury is a serve trauma. For the reason of its conventional therapeutic efficacy not well, a lot of patients remained sequela such as dyskinesia, sensory disability, dysfunction of bladder and rectum. Neurotrophic factor is essential material for nerve injury recovery and functional reconstruction.To begin with correlated molecule mechanism of endogenous NT-3 and its receptor TrkC expression,,exploring new strategy to promote spinal injury recovery is one of significance content about international neuroscience researching area.
Objective:
To investigate the phase changes of NT-3 and TrkC from relative motor neurons in injury segment bilateralis of adult Sprague-Dawley rats subjected to cord transection by both immunohistochemistry, Western blotting and RT-PCR, and also give primary discussion about the temporal changes and endogenous action mechanisms of endogenous NT-3 and TrkC following transected spinal cord injury,and make understanding its relationship with plasticity of spinal cord.
Method:
Adult female Sprague-Dawley rats (200g-220g) were used in our study. Adult SD rats were divided into six groups randomly with seven rats each group.One group is sham operation and the other groups for spinal cord transaction. Spinal cord transection were performed at T9 to T10 level in rats from five groups, while control group did not receive transection of the spinal cord. The rats received spinal cord transection were allowed to survive for 1 days,3 days,7 days,14days and 28days.While the time point reach,experimental rats were sacrificed. Seven tissue sample were removed such as two sides cerebral cortex, midbrain,4 columns from caudal and rostral ambi-1 cm spinal cord around the injury site corresponding T8 to T11 level. After perfusion, Samples from 3 rats each group were processed for NT-3 and TrkC immunohistochemistry. And then, fresh sample from 2 rats each group were obtained for the use of sem-qualification by western blotting and qualification by RT-PCR. Hindlimb function was evaluated and recorded after operation. Through postfix and dehydration,The sample for immunohistochemistry was cut to 20μm thick frozen sections. By the irnrnunohistochemical SP and fluorescence staining method, we observed the morphology,distribution and subcellular localization of NT-3 and TrkC immununoreactive cells in the ventral horn of the spinal cord and the motor area of the cerebrum. The immunoreactive cells were counted and the Optical densities (OD) were measured. The protein of NT-3 and TrkC was measured by western blotting method for sem-qualification. The mRNA of NT-3 and TrkC was measured by RT-PCR for qualification.The data were statistically anaiysed with one-way ANOVA and LSD test using SPSS 13.0 statistical package.
Result:
1. Western blotting strap specificity recogniting molecular mass 13.6Kda and 145Kda corresponded molecular mass of NT-3 and TrkC respectively. Replace experiment and negative control experiment is negative.
2.According to the irnrnunohistochemical outcome, Varying intensities of NT-3 and TrkC immnuostaining were observed in a wide variety of motor neurons, endaxoneuron and glial cells in the rat central nervous system. Through sem-qualification by western blotting, The most high concentration of NT-3 was detected in brainstem and hippocampus of rat brains.
3. The dense NT-3 and TrkC positive products can be observed in the cytoplasm and processes of neurons in sham group and experimental groups.The nuclei and cytoplasm were labeled by NT-3 antibodies.Robust labeling of NT-3 were detected in nuclei. The dense TrkC positive products can be observed in the cytoplasm of neurons, but very few in the processes and nerve terminal, not be observed in the motor cortex.After spinal cord injury, the nuclei stain intensificated obviously and also been observed in some arborescence branch and neurite,but not be observed in centre motor cortex of brain.
4. (1)The means of NT-3 positive neurons from caudal and rostral spinal cord around the injury site have significant deviation (P<0.001). The means of NT-3 positive neurons from cornu anterius medullae spinalis in each experimental group have significant deviation versus sham group (P<0.05). Positive neurons with NT-3 were sharply decreased in 1ST day after SCI. After 1ST day, the number of the NT-3 positive neurons were constantly increasing, at the end of 28th,maintaining the increase tendency. The means of NT-3 positive neurons from caudal and rostral spinal cord around the injury site in each group have no significant deviation (P=0.184-1.000). (2) The means of TrkC positive neurons from caudal and rostral spinal cord around the injury site have shown down regulation versus sham group in 1ST day and 7ST day after SCI, and then,have recovered to the level of sham group in 14ST day and 28ST day after SCI.The expression level of TrkC from rostral was higher than caudal significantly. The expression level of TrkC from injury segment was higher than consecutive segment significantly. Sem-qualification by western blotting can not detected TrkC protein in motor cortex of brain. (3)Resembling to the changes of TrkC protein, mRNA level of TrkC was decreased significantly from 1ST day to 7ST day after SCI versus sham group, but recovered to super-level of sham group in 14ST day.Contrasting sham group, The expression of TrkC mRNA remained a lower level in motor cortex of brain at different time point. (4) The OD of NT-3 and TrkC in cornu anterius medullae spinalis had been a similar tendency with the changes of irnrnunohistochemistry after SCI.
5.Immunoreactivities of NT-3 positive neurons in the fore motor area of cerebral cortex had been a similar tendency with the changes of the motoneurons in the ventral horn after SCI.
6. The BBB score of the sham-operated and normal rats were 21, after spinal cord transection, the rats showed complete paralysis (0), however, spontaneous functional recovery of the rats'hindlimbs occurred during the time-course, and peaked at 28d (2.57).
Conclusion:
1. Our antibodies identification experiments showed that the antisera were specific for the appropriate neurotrophin and did not cross react with other neurotrophins.
2. NT-3 and TrkC were distributed in motor neurons in limited regions of adult brains of rats. NT-3 likewise its receptor TrkC, in majority of regions of rodents brains and ventral horn, having the overlapping expression, but differences also exits,and so did the expression of TrkC. All above indicated NT-3 and TrkC participate the physiological function of nerve cells in the brain and spinal cord of rodents, nevertheless, they performed different action respectively in different region.
3. The temporal changes differences between the positive neurons with NT-3 and that with TrkC after SCI, indicating the expression of NT-3 and TrkC have the relation to the recovery after SCI. However, some discrepancies also can be observed for their mode of action in different time course after SCI. It can offer some theory based on experiment for clinic using NTFs to cure spinal cord injury.
引文
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