非甾体抗炎药对大鼠神经根慢性压迫性损伤诱导的脊髓神经细胞凋亡的影响
摘要
非甾体抗炎药对大鼠神经根慢性压迫性损伤诱导的脊髓神经细胞凋亡的影响
前言
细胞凋亡在中枢神经损伤中的作用越来越受到重视,近年来有关周围神经损伤与凋亡的文献也陆续出现。本实验检测了大鼠神经根慢性损伤后脊髓神经细胞的凋亡率,同时探讨了不同类型非甾体抗炎药(NSAIDs)对此的影响,试图结释腰椎管狭窄症的一些不典型症状,也为NSAIDs在脊柱外科中的应用提供一点参考。
研究对象和方法
将48只SD大鼠随机分为对照组、结扎组、吲哚美辛组和美洛昔康组各12只。在结扎组,切除右侧椎板后在右侧L5神经根出口处用丝线环绕疏松结扎,造成神经根慢性压迫性损伤模型,术后进行神经损伤评分,饲养4周处死,经灌注固定及后固定,取L5神经根相连的脊髓节段、其头侧6mm及脊髓圆锥,制成5um切片,切片操作包括HE染色,TUNEL染色标记凋亡细胞,以及免疫组织化学方法。吲哚美辛组和美洛昔康组的模型、切片制备与结扎组相同,术后分别喂服吲哚美辛(消炎痛)、美洛昔康(莫比可)。对照组切除椎板后在右侧L5神经根出口处用丝线环绕神经根后将线尾留置而不结扎,其余的处理与结扎组相同。
结果
结扎组、吲哚美辛组和美洛昔康组大鼠在术后1周左右均出现了不同程度神经损伤症状;3个组的神经损伤评分均无统计学差异(P>0.05);在结扎组,凋亡指数与神经损伤评分之间存在正相关(Spearman,2-tailed,0.01 level,r=0.858,P<0.01)。TUNEL染色结果显示对照组有极少量阳性细胞被标记到;结扎组有一定量的前角运动神经元被标记,分布范围主要集中在右侧L5神经根相连的脊髓组织,左侧相应的节段亦有散在的阳性细胞被标记,与对照组比较有非常显著差异(P<0.01);吲哚美辛组和美洛昔康组均可标记到少量阳性细胞,与对照组比较均无统计学差异(P>0.05),与结扎组比较均有非常显著差异(P<0.01),吲哚美辛组和美洛昔康组之间无统计学差异(P>0.05)。免疫组化法显示对照组bcl-2蛋白和Bax蛋白少量表达;结扎组Bax蛋白表达明显增高,bcl-2蛋白表达没有改变;吲哚美辛组和美洛昔康组bcl-2蛋白Bax蛋白亦有少量表达;结扎组Bax蛋白表达与各组比较均有非常显著差异(P<0.01);各组bcl-2蛋白表达均无统计学差异(P>0.05)。
结论
神经根慢性压迫性损伤可以引起发出该神经根的脊髓节段前角运动神经元凋亡,与损伤程度正相关,可能的机制:神经根的慢性压迫性损伤最终使中枢神经细胞生存信号缺失或失营养,触发细胞程序性死亡;非选择性COX抑制剂吲哚美辛和选择性COX-2抑制剂美洛昔康均可抑制脊髓神经细胞的凋亡,提示NSAIDs抗神经细胞凋亡的机制与其抑制COX的哪一种亚型无关;NSAIDs未明显改善大鼠的神经损伤症状。
The Influence of NSAIDs on Spinal Cord Nerve Cells Apoptosis in Rats Induced by Chronic Compressive Nerve Root Injury
Foreword
The role of apoptosis in the central nerve system injury was more and more emohasized.There come out a few literatures about peripheral nerve injury and cells in rats induced by chronic nerve root injury,and investigate the influences on it by the different types of NSAIDs,so trying to explain some atypical symptoms of the lumbar spinal stenosis syndrome,and also to provide some references fo the application of the NSAIDs in the spinal surgeries.
Subjects and methods
48 SD rats were arranged to four groups,they are Control group,Ligation group. Indometacin group,and Meloxicam group,and each group has 12 rats.In the Ligation group,the right L5 root of each rat was ligated loosely at the exit after right laminectoy, to create a chronic compressive model of the spinal nerve;evaluate the degree of spinal nerve injury after surgery;put the rats to death after 4 weeks,then the spinal cord segment was made into 5um slices connected with the L5 spinal nerve including the part 6mm to head and conus medullaris,these slices were dyed by HE and TUNEL method to mark the apoptosis cells and were investigated by the immunohistochemical method.This method was also applied in the Indometacin group and Meloxicam group, then the rats in this two group were fed by Indometacin and Meloxicam respectively after the surgery.In the Control group,the nerve roots were surrounded by the thread but not ligated at the exit,the reminder operations were the same as the ligation group.
Results
The rats appear nerve injury symptoms in different degrees in the Ligation, Indometacin and Meloxicam group about one week after sugery;the nerve injury scores in this three groups were not different(P>0.05);in the Ligation,there is apositive correlation between Apptotic Index and nerve injury scores(Spearman,2-tailed,0.01 level,r=0.0858,P<0.01).The results by TUNNEL dye appeared that a few positive cells were marked in the Ligation,distributing scope centralizes at the right side of the spinal cord connected L5 nerve root and its adjacent segment,there were also some positive cells marked dispersedly in the left side,and there was significant differences with the Control(P<0.01);a few positive cells were marked in the Indometacin and the Meloxicam group,there is no statistical difference with the Control(P>0.05),but there are significant differences between the two groups and the Ligation(P<0.01),and no statistical difference between the Indometacin group and Meloxicam group(P>0.05). On the immunohistochemical method,there is a little expression of the bcl-2 and Bax protein in the Control,a significant increasing expression of Bax protein and no expression of bcl-2 protein in the Ligation,a little expression of bcl-2 and Bax protein in the Indometacin and Meloxicam group.
Conclusion
The chronic compressive injury of the nerve root can result in spinal anterior angle moto neurons apoptosis of this spinal cord segment connected to the nerve root,and there was a positive correlation with the injury degrees;the possible mechanisms is that the living signals and nutritions of the central nerval cells lost because of the chronic pression injuries,and triggered the cell processional death.Nonselective COX inhibitor-Indometacin and selective COX-2 inhibitor-Meloxicam both can prevent the spinal nerve cells from apoptosis.The results indicated that the mechanisms of inhibiting nerve cells apoptosis by NSAIDs are independent to the isoforms of COX; and NSAIDs didn't improve nerve injury symptoms of the rats.
前言
细胞凋亡在中枢神经损伤中的作用越来越受到重视,近年来有关周围神经损伤与凋亡的文献也陆续出现。本实验检测了大鼠神经根慢性损伤后脊髓神经细胞的凋亡率,同时探讨了不同类型非甾体抗炎药(NSAIDs)对此的影响,试图结释腰椎管狭窄症的一些不典型症状,也为NSAIDs在脊柱外科中的应用提供一点参考。
研究对象和方法
将48只SD大鼠随机分为对照组、结扎组、吲哚美辛组和美洛昔康组各12只。在结扎组,切除右侧椎板后在右侧L5神经根出口处用丝线环绕疏松结扎,造成神经根慢性压迫性损伤模型,术后进行神经损伤评分,饲养4周处死,经灌注固定及后固定,取L5神经根相连的脊髓节段、其头侧6mm及脊髓圆锥,制成5um切片,切片操作包括HE染色,TUNEL染色标记凋亡细胞,以及免疫组织化学方法。吲哚美辛组和美洛昔康组的模型、切片制备与结扎组相同,术后分别喂服吲哚美辛(消炎痛)、美洛昔康(莫比可)。对照组切除椎板后在右侧L5神经根出口处用丝线环绕神经根后将线尾留置而不结扎,其余的处理与结扎组相同。
结果
结扎组、吲哚美辛组和美洛昔康组大鼠在术后1周左右均出现了不同程度神经损伤症状;3个组的神经损伤评分均无统计学差异(P>0.05);在结扎组,凋亡指数与神经损伤评分之间存在正相关(Spearman,2-tailed,0.01 level,r=0.858,P<0.01)。TUNEL染色结果显示对照组有极少量阳性细胞被标记到;结扎组有一定量的前角运动神经元被标记,分布范围主要集中在右侧L5神经根相连的脊髓组织,左侧相应的节段亦有散在的阳性细胞被标记,与对照组比较有非常显著差异(P<0.01);吲哚美辛组和美洛昔康组均可标记到少量阳性细胞,与对照组比较均无统计学差异(P>0.05),与结扎组比较均有非常显著差异(P<0.01),吲哚美辛组和美洛昔康组之间无统计学差异(P>0.05)。免疫组化法显示对照组bcl-2蛋白和Bax蛋白少量表达;结扎组Bax蛋白表达明显增高,bcl-2蛋白表达没有改变;吲哚美辛组和美洛昔康组bcl-2蛋白Bax蛋白亦有少量表达;结扎组Bax蛋白表达与各组比较均有非常显著差异(P<0.01);各组bcl-2蛋白表达均无统计学差异(P>0.05)。
结论
神经根慢性压迫性损伤可以引起发出该神经根的脊髓节段前角运动神经元凋亡,与损伤程度正相关,可能的机制:神经根的慢性压迫性损伤最终使中枢神经细胞生存信号缺失或失营养,触发细胞程序性死亡;非选择性COX抑制剂吲哚美辛和选择性COX-2抑制剂美洛昔康均可抑制脊髓神经细胞的凋亡,提示NSAIDs抗神经细胞凋亡的机制与其抑制COX的哪一种亚型无关;NSAIDs未明显改善大鼠的神经损伤症状。
The Influence of NSAIDs on Spinal Cord Nerve Cells Apoptosis in Rats Induced by Chronic Compressive Nerve Root Injury
Foreword
The role of apoptosis in the central nerve system injury was more and more emohasized.There come out a few literatures about peripheral nerve injury and cells in rats induced by chronic nerve root injury,and investigate the influences on it by the different types of NSAIDs,so trying to explain some atypical symptoms of the lumbar spinal stenosis syndrome,and also to provide some references fo the application of the NSAIDs in the spinal surgeries.
Subjects and methods
48 SD rats were arranged to four groups,they are Control group,Ligation group. Indometacin group,and Meloxicam group,and each group has 12 rats.In the Ligation group,the right L5 root of each rat was ligated loosely at the exit after right laminectoy, to create a chronic compressive model of the spinal nerve;evaluate the degree of spinal nerve injury after surgery;put the rats to death after 4 weeks,then the spinal cord segment was made into 5um slices connected with the L5 spinal nerve including the part 6mm to head and conus medullaris,these slices were dyed by HE and TUNEL method to mark the apoptosis cells and were investigated by the immunohistochemical method.This method was also applied in the Indometacin group and Meloxicam group, then the rats in this two group were fed by Indometacin and Meloxicam respectively after the surgery.In the Control group,the nerve roots were surrounded by the thread but not ligated at the exit,the reminder operations were the same as the ligation group.
Results
The rats appear nerve injury symptoms in different degrees in the Ligation, Indometacin and Meloxicam group about one week after sugery;the nerve injury scores in this three groups were not different(P>0.05);in the Ligation,there is apositive correlation between Apptotic Index and nerve injury scores(Spearman,2-tailed,0.01 level,r=0.0858,P<0.01).The results by TUNNEL dye appeared that a few positive cells were marked in the Ligation,distributing scope centralizes at the right side of the spinal cord connected L5 nerve root and its adjacent segment,there were also some positive cells marked dispersedly in the left side,and there was significant differences with the Control(P<0.01);a few positive cells were marked in the Indometacin and the Meloxicam group,there is no statistical difference with the Control(P>0.05),but there are significant differences between the two groups and the Ligation(P<0.01),and no statistical difference between the Indometacin group and Meloxicam group(P>0.05). On the immunohistochemical method,there is a little expression of the bcl-2 and Bax protein in the Control,a significant increasing expression of Bax protein and no expression of bcl-2 protein in the Ligation,a little expression of bcl-2 and Bax protein in the Indometacin and Meloxicam group.
Conclusion
The chronic compressive injury of the nerve root can result in spinal anterior angle moto neurons apoptosis of this spinal cord segment connected to the nerve root,and there was a positive correlation with the injury degrees;the possible mechanisms is that the living signals and nutritions of the central nerval cells lost because of the chronic pression injuries,and triggered the cell processional death.Nonselective COX inhibitor-Indometacin and selective COX-2 inhibitor-Meloxicam both can prevent the spinal nerve cells from apoptosis.The results indicated that the mechanisms of inhibiting nerve cells apoptosis by NSAIDs are independent to the isoforms of COX; and NSAIDs didn't improve nerve injury symptoms of the rats.
引文
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27 Kishimoto Y,Yashima K,Morisawa T,et al.Effects of long-term administration of sulindac on APC Mrna and apoptosis in colons of rats treated with azoxymethane,J Cancer Res Clin Oncol 2002 Nov:128(11):589-95.
28 Moore BC,Simmons DL.COX-2inhibition,apoptosis,and chemoprevention by nonssteroidal anti-inflammatory drugs.Curr Med Chem 2000 Nov;7(11):1131-44.
29 X.Zhang,F.Dong,G.E.Mayer,et al.Selective Inhibition of COX-2 Exacerbates Methampheta-mine-Induced Dopamine Depletion in The Sreiatum in Rats.[J].Neuroscience.2007;150:950-958.
30 Moro MA,De-Alba J,Cardens A,et al.Mechanisms of the neuroprotective effect of aspirin after oxygen and glucose deprivation in rat forebrain slices.[J]Neuropharmacology 2000;39(7):1309-1318.
2 朱国萍,娄阳,徐冲.BCL-2蛋白家族与细胞凋亡.细胞生物学杂志.2004,23(1):20-23.
3 Orrenius S,Nicotera P.The caicium ion and cell death.J Neural Transm,1994,43 Suppl:1-11.
4 王贵波,李兵仓,王建民,等.兔坐骨神经火器伤后腰段脊髓脂质过氧化反应及意义.中国急救医学.2002;22:1-3.
5 Azkue JJ,Zimmermann M,Hsieh TF,et al.Peripheral nerve insult induces NMDA receptormediated,delayed degeneration in spinal neurons.Eur J Neurosci 2001 Jun;10(6):2204-6.
6 Gordh T,Sharma HS,Alm P,et al.Spinal nerve lesion induces upregulation of neuronal nitric oxide synthase in the spinal cord:an immunohistochemical investigation in the rat.Amino Acids 2001;14:105-112.
7 Groves MJ,An SF,Giometto B,Scaravilli F.Inhibition of sensory neuron apoptosis and ptevention of loss by NT-3 administration following axotomy.Exp Neurol 2005 Feb;155(2):294-94
8 Iwasaki Y,Shiojima T,Tagaya N,et al.Basic fibroblast growth factor and platelet-derived growth factor prevent the death of spinal motor neutone after sciatic nerve transection in the neonatal rats.Neurol 2004;19:555-557.
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