汉防己甲素对大鼠急性脊髓损伤后神经保护作用的机制研究
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摘要
急性脊髓损伤(acute spinal cord injury, ASCI)在病理上表现为白质和灰质的损伤，现在普遍认为由原发性损伤和随着出现的继发性损伤造成，继发性损伤是在原发性损伤发生后数分钟内到数天，序贯发生的复杂的自我毁灭的级联反应的过程，其中ASCI后诱发的免疫炎性反应在继发性损伤中起着极其重要的作用，可导致损伤区残余的神经细胞及邻近组织的神经细胞死亡及凋亡，同时在损伤脊髓的微环境中存在抑制内源性神经干细胞增殖分化的负性因素，是造成脊髓功能障碍持续加重且功能恢复不好的主要原因。随着脊髓损伤机制研究的深入，认为继发性损伤有可干预性，在早期减轻继发性损伤能保护残余脊髓组织、促进脊髓功能的修复。汉防己甲素(tetrandrine,Tet)是中药防己的有效成分，大量研究证明其具有抗炎、抗脂质过氧化、防止细胞受损、改善微循环及Ca2+拮抗作用。本实验设计主要探讨Tet能否通过ASCI后炎症介质的调节作用、凋亡的抑制作用及其对内源性神经干细胞增殖分化的影响来促进ASCI后神经功能的恢复，为Tet应用于临床治疗ASCI提供进一步的理论依据。
第一部分汉防己甲素对大鼠脊髓损伤后神经细胞凋亡的影响
目的：观察Tet对大鼠急性脊髓损伤后神经细胞凋亡的影响。
方法：选用114只成年大鼠，随机分为四组，即假手术组6只（A组）、损伤组（B组）36只、甲基强的松龙治疗组（C组）36只、Tet治疗组（D组）36只。胸8、9、10椎板切除后，B、C、D组用Allen重物下落打击法制备脊髓损伤模型。C组和D组动物于制模术后30分钟、伤后24h、伤后48h尾静脉注射甲基强的松龙(MP)和Tet。各组大鼠于术后8h,1d,3d,7d,14d、28d行BBB评分，分别于术后8h,1d,3d,7d,14d、28d取损伤段脊髓行石蜡切片HE染色观察脊髓组织的形态结构变化和免疫组织化学染色检测细胞凋亡因子bcl-2、bax的表达以及运用流式细胞仪对标本进行凋亡细胞的半定量分析。
结果：伤后7d、14d、28dC组与D组大鼠运动功能评分(BBB评分)显著高于B组，各时间点C组与D组评分无统计学意义；A组的脊髓组织HE染色正常，C组与D组脊髓组织损害较B组轻，术后8h-28d动态观察，3d—7d损伤表现最为严重，达到损伤高峰期；A组中bax、bcl-2表达较少，C组与D组bax表达较B组少，而bcl-2表达较B组多。凋亡细胞半定量分析示B、C、D组均在损伤后7d达凋亡细胞数峰值，之后逐渐减少，各组间同一时点比较，Tet组明显少于ASCI组，有统计学意义，略多于Mp组，两组相较无统计学意义。
结论：汉防己甲素可通过增加bcl-2表达、降低bax表达，抑制急性脊髓损伤后神经细胞的凋亡，有益于脊髓组织的保护，促进运动功能的恢复。第二部分汉防己甲素对大鼠急性脊髓损伤后炎症性因子的影响
目的：探讨ASCI后早期运用Tet治疗对炎症性因子释放的影响。
方法：选用78只成年大鼠，随机分为三组，即假手术组6只、损伤对照组36只、Tet治疗组（D组）36只。胸8、9、10椎板切除后，损伤组及Tet组用Allen重物下落打击法制备脊髓损伤模型。Tet组动物于制模术后30分钟、伤后24h、伤后48h尾静脉注射Tet。各组大鼠分别于术后6h,12h,1d,3d,5d,7d取损伤段脊髓用酶联免疫吸附法行TNF-α,IL-1β,IL-6,IL-10,NF-kB含量的检测。
结果：ASCI后6h、12h、1d、3d、5d、7d损伤对照组和Tet组TNF-α,IL-1β,IL-6,IL-10,NF-kB含量高于假手术组，ASCI后6h即有明显的增加，在24h-72h达到高峰，5天时开始下降，Tet组IL-10含量高于损伤对照组，而TNF-α,IL-1β,IL-6,NF-kB含量低于损伤对照组。
结论：脊髓损伤能增加伤段TNF-α,IL-1β,IL-6,IL-10,NF-kB的含量，汉防己甲素可通过增加损伤脊髓中IL-10的含量、降低TNF-α,IL-1β,IL-6,NF-kB的含量，改善局部微环境，有益于脊髓组织的保护。
第三部分探讨汉防已甲素对内源性神经干细胞增殖分化的影响
目的：探讨Tet对大鼠ASCI后脊髓损伤段ENSC增殖分化的影响。
方法：选用78只大鼠，随机分为3组：损伤对照组(n=36只)，Tet组(n=36只),假手术组(n=6)。损伤组、Tet组采用Allen’s打击法造模，Tet组于脊髓损伤后30分钟、术后24h、术后48h给予Tet22.5mg/kg体重治疗，损伤组注射同等剂量的生理盐水。于脊髓损伤伤后1d、3d、1w、2w、3w、4w取损伤段脊髓组织，用免疫荧光组织化学方法检测各组大鼠脊髓组织在不同时间段Nestin及BrdU的表达变化情况。
结果：ASCI后1天时损伤对照组及Tet组均可见少量Nestin表达阳性细胞及BrdU表达阳性细胞，ASCI1周损伤对照组及Tet组可见大量阳性细胞，阳性细胞表达达高峰，持续至2周后逐渐开始下降，ASCI后4周时，Tet组、损伤对照组中BrdU及Nestin阳性细胞表达数明显减少，但仍较假手术组高。Tet组BrdU阳性细胞数量和Nestin阳性细胞数量在各时间点均高于损伤对照组。损伤对照组及Tet组在ASCI后1d、3d、1w、2w、3w时与假手术组相比BrdU、Nestin阳性细胞数量差异有统计学意义。损伤对照组及Tet组在ASCI后1d、3d、1w、2w、3w时BrdU、Nestin阳性细胞数量差异有统计学意义。
结论：Tet通过改善微环境能增加BrdU、Nestin阳性细胞，增加ENSCs的增殖，有利于神经功能的恢复。
Acute spinal cord injury(ASCI) manifests injury on white and graymatter in pathology, which results in primary injury and secondary lesion.The secondary lesion is a complicate cascade reaction several minutes todays after primary injury, and the immune inflammation reaction afterASCI plays a important role in secondary lesion. The immuneinflammation reaction after ASCI can result in the reside and adjacentnerve cells death and apoptosis, at the same time the micro environment ininjury spinal cord exits negative factors which can inhabit neural stem cellproliferation, and it is the main reason that recover bad after ASCI. Withstudy further on the mechanism of ASCI, the secondary lesion is realizedcould be intervened. It can protect residue spinal cord and promote thefunction of spinal cord recovery. The tetrandrine(TET) is the effectiveingredients of Radix Stephaniae Tetrandrae. A lot of research prove it canagainst inflammation and lipid peroxidation, prevent cell injury, improvemicrocirculation, and antagonize the Ca2+.Our study discuss if the TET could promote the function of spinal cord recovery through adjust theinflammation factors, inhabit the cell apoptosis and infect on neural stemcell proliferation, and provide theory proof for TET treat ASCI.
PART ONE: EFFECT OF TETRANDRINE ON CELL APOPTOSISFOLLOWING ACUTE SPINAL CORD INJURY IN RATS
Objective:To observe the influence of tetrandrine on cell apoptosisfollowing spinal cord injury in rats.
Methods:114SD rats were randomly divided into three groups:sham group(group A),control group(group B),methylprednisolone(MP)group(group C) and tetrandrine(Tet) group(group D).The modified Allenmethod was adopted to make the models of T9spinal cord injury in B andC and D group. BBB score was recorded at8h,1d,3d,,7d,14d,28drespectively. The samples were taken from the spinal cord injury sites at8h,1d,3d,7d,14d,28d tested by HE staining for morphology and detectedthe expression levels of Bcl-2、Bax protein by immunohistochemistryassay. The semi-quantitative analysis for apoptosis nerve cells can begained by the flow cytometry (FCM).
Results:The BBB score of group C and D were significantly higherthan that of group B at7,14and28day time point. HE stain showed thespinal cord of group C and D has fewer necrosis than that of group B. Thenumber of Bcl-2postive cells in group C and D were significantly higherthan those of group B at each time points. However the number of Baxpostive cells in group C and D were significantly lower than those of groupB at each time points.
Conclusions: Tetrandrine can prevent neurons from apoptosis andpromote the nerve function recover by inhibiting the expression of Bax and promoting the expression of Bcl-2.
PART TWO: EFFECT OF TETRANDRINE ON RELEASE OFINFLAMMATORY FACTOR FOLLOWING ACUTE SPINALCORD INJURY IN RATS
Objective:To observe the influence of tetrandrine on release ofinflammatory factor following spinal cord injury in rats.
Methods:78SD rats were randomly divided into:shamgroup,control group, Tet group.The modified Allen method was adopted tomake the models of T9spinal cord injury in control group and Tet group.The samples were taken from the spinal cord injury sites at6h,12h,1d,3d,5d,7ddetected the contents of TNF-α,IL-1β,IL-6,IL-10,NF-kBby using enzyme-linked immunosorbent assay.
Results: The expression of TNF-α, IL-1β, IL-6, IL-10, NF-kB ininjury control group and Tet group at6h,12h,1d,3d,5d,7d After ASCI washigher than that in sham operation group, has obviously increased at6hafter ASCI, peaked at24h-72h, began to decrease at5day after ASCI,.Theexpression of IL-10in Tet group was higher than the control group,but theexpression of TNF-α, IL-1β, IL-6, NF-kB is lower than the control group.
Conclusion:The content of TNF-α,IL-1β,IL-6,IL-10,NF-kB wasincrease in the spinal cord. Tetrandrine is able to improve local microenvironment and promote the nerve function recover by increasing theexpression of IL-10and decreasing the expression of TNF-α,IL-1 β,IL-6,NF-kB in the spinal cord injury.
PART THREE: EXPERIMENTAL STUDY ON EFFECT OFTETRANDRINE IN THE ENDOGENOUS NEURAL STEM CELLPROLIFERATION AND DIFFERENTIATION AFTER SPINALCORD INJURY IN RATS
Objective: Discuss the effects of tetrandrine on the endogenousneural stem cell proliferation and differentiation after spinal cord injury inrats.
Methods:78rats were randomly divided into3groups: injuriedgroup (n=36), Tet-treated group (n=36),sham-operated group (n=6).Injuried group and Tet-treated group damage spinal cord with Allen 'scombat modeling method.30minutes after damage, Tet was injected with adosage22.5mg/kg in Tet group at30minutes,24h and48h after ASCI, andthe same dosement of saline was injected in injuried group as control. Thesamples were dissected from the spinal cord injury sites at1d,3d,1w,2w,3w,4w and detected the expression of BrdU and nestin byimmunofluorescence staining.
Results: A little nestin positive cells and brdU positive cells werefound in injuried group and Tet-treated group at1day after injury. A largenumber of positive cells were found in both groups at one week after injuryand reached the peak which lasted for2weeks and then decreasedgradually. The expression of Nestin positive cells and brdU positive cells decreased significantly at4weeks after injury. Compared with the shamoperation group, the number of Nestin positive cells and brdU positive cellswas more in injuried group and Tet-treated group at1d,3d,1W,2W,3W afterinjury. The expression was higher in Tet-treated group than injuried groupat1d,3d,1w,2w,3w after injury and had no difference at4weeks afterinjury.
Conclusion: It was concluded that tetrandrine could increase thenumber of Nestin positive cells, brdU positive cells and endogenous neuralstem cells.It is beneficial to the recovery of spinal cord injury in rats.
第一部分汉防己甲素对大鼠脊髓损伤后神经细胞凋亡的影响
目的：观察Tet对大鼠急性脊髓损伤后神经细胞凋亡的影响。
方法：选用114只成年大鼠，随机分为四组，即假手术组6只（A组）、损伤组（B组）36只、甲基强的松龙治疗组（C组）36只、Tet治疗组（D组）36只。胸8、9、10椎板切除后，B、C、D组用Allen重物下落打击法制备脊髓损伤模型。C组和D组动物于制模术后30分钟、伤后24h、伤后48h尾静脉注射甲基强的松龙(MP)和Tet。各组大鼠于术后8h,1d,3d,7d,14d、28d行BBB评分，分别于术后8h,1d,3d,7d,14d、28d取损伤段脊髓行石蜡切片HE染色观察脊髓组织的形态结构变化和免疫组织化学染色检测细胞凋亡因子bcl-2、bax的表达以及运用流式细胞仪对标本进行凋亡细胞的半定量分析。
结果：伤后7d、14d、28dC组与D组大鼠运动功能评分(BBB评分)显著高于B组，各时间点C组与D组评分无统计学意义；A组的脊髓组织HE染色正常，C组与D组脊髓组织损害较B组轻，术后8h-28d动态观察，3d—7d损伤表现最为严重，达到损伤高峰期；A组中bax、bcl-2表达较少，C组与D组bax表达较B组少，而bcl-2表达较B组多。凋亡细胞半定量分析示B、C、D组均在损伤后7d达凋亡细胞数峰值，之后逐渐减少，各组间同一时点比较，Tet组明显少于ASCI组，有统计学意义，略多于Mp组，两组相较无统计学意义。
结论：汉防己甲素可通过增加bcl-2表达、降低bax表达，抑制急性脊髓损伤后神经细胞的凋亡，有益于脊髓组织的保护，促进运动功能的恢复。第二部分汉防己甲素对大鼠急性脊髓损伤后炎症性因子的影响
目的：探讨ASCI后早期运用Tet治疗对炎症性因子释放的影响。
方法：选用78只成年大鼠，随机分为三组，即假手术组6只、损伤对照组36只、Tet治疗组（D组）36只。胸8、9、10椎板切除后，损伤组及Tet组用Allen重物下落打击法制备脊髓损伤模型。Tet组动物于制模术后30分钟、伤后24h、伤后48h尾静脉注射Tet。各组大鼠分别于术后6h,12h,1d,3d,5d,7d取损伤段脊髓用酶联免疫吸附法行TNF-α,IL-1β,IL-6,IL-10,NF-kB含量的检测。
结果：ASCI后6h、12h、1d、3d、5d、7d损伤对照组和Tet组TNF-α,IL-1β,IL-6,IL-10,NF-kB含量高于假手术组，ASCI后6h即有明显的增加，在24h-72h达到高峰，5天时开始下降，Tet组IL-10含量高于损伤对照组，而TNF-α,IL-1β,IL-6,NF-kB含量低于损伤对照组。
结论：脊髓损伤能增加伤段TNF-α,IL-1β,IL-6,IL-10,NF-kB的含量，汉防己甲素可通过增加损伤脊髓中IL-10的含量、降低TNF-α,IL-1β,IL-6,NF-kB的含量，改善局部微环境，有益于脊髓组织的保护。
第三部分探讨汉防已甲素对内源性神经干细胞增殖分化的影响
目的：探讨Tet对大鼠ASCI后脊髓损伤段ENSC增殖分化的影响。
方法：选用78只大鼠，随机分为3组：损伤对照组(n=36只)，Tet组(n=36只),假手术组(n=6)。损伤组、Tet组采用Allen’s打击法造模，Tet组于脊髓损伤后30分钟、术后24h、术后48h给予Tet22.5mg/kg体重治疗，损伤组注射同等剂量的生理盐水。于脊髓损伤伤后1d、3d、1w、2w、3w、4w取损伤段脊髓组织，用免疫荧光组织化学方法检测各组大鼠脊髓组织在不同时间段Nestin及BrdU的表达变化情况。
结果：ASCI后1天时损伤对照组及Tet组均可见少量Nestin表达阳性细胞及BrdU表达阳性细胞，ASCI1周损伤对照组及Tet组可见大量阳性细胞，阳性细胞表达达高峰，持续至2周后逐渐开始下降，ASCI后4周时，Tet组、损伤对照组中BrdU及Nestin阳性细胞表达数明显减少，但仍较假手术组高。Tet组BrdU阳性细胞数量和Nestin阳性细胞数量在各时间点均高于损伤对照组。损伤对照组及Tet组在ASCI后1d、3d、1w、2w、3w时与假手术组相比BrdU、Nestin阳性细胞数量差异有统计学意义。损伤对照组及Tet组在ASCI后1d、3d、1w、2w、3w时BrdU、Nestin阳性细胞数量差异有统计学意义。
结论：Tet通过改善微环境能增加BrdU、Nestin阳性细胞，增加ENSCs的增殖，有利于神经功能的恢复。
Acute spinal cord injury(ASCI) manifests injury on white and graymatter in pathology, which results in primary injury and secondary lesion.The secondary lesion is a complicate cascade reaction several minutes todays after primary injury, and the immune inflammation reaction afterASCI plays a important role in secondary lesion. The immuneinflammation reaction after ASCI can result in the reside and adjacentnerve cells death and apoptosis, at the same time the micro environment ininjury spinal cord exits negative factors which can inhabit neural stem cellproliferation, and it is the main reason that recover bad after ASCI. Withstudy further on the mechanism of ASCI, the secondary lesion is realizedcould be intervened. It can protect residue spinal cord and promote thefunction of spinal cord recovery. The tetrandrine(TET) is the effectiveingredients of Radix Stephaniae Tetrandrae. A lot of research prove it canagainst inflammation and lipid peroxidation, prevent cell injury, improvemicrocirculation, and antagonize the Ca2+.Our study discuss if the TET could promote the function of spinal cord recovery through adjust theinflammation factors, inhabit the cell apoptosis and infect on neural stemcell proliferation, and provide theory proof for TET treat ASCI.
PART ONE: EFFECT OF TETRANDRINE ON CELL APOPTOSISFOLLOWING ACUTE SPINAL CORD INJURY IN RATS
Objective:To observe the influence of tetrandrine on cell apoptosisfollowing spinal cord injury in rats.
Methods:114SD rats were randomly divided into three groups:sham group(group A),control group(group B),methylprednisolone(MP)group(group C) and tetrandrine(Tet) group(group D).The modified Allenmethod was adopted to make the models of T9spinal cord injury in B andC and D group. BBB score was recorded at8h,1d,3d,,7d,14d,28drespectively. The samples were taken from the spinal cord injury sites at8h,1d,3d,7d,14d,28d tested by HE staining for morphology and detectedthe expression levels of Bcl-2、Bax protein by immunohistochemistryassay. The semi-quantitative analysis for apoptosis nerve cells can begained by the flow cytometry (FCM).
Results:The BBB score of group C and D were significantly higherthan that of group B at7,14and28day time point. HE stain showed thespinal cord of group C and D has fewer necrosis than that of group B. Thenumber of Bcl-2postive cells in group C and D were significantly higherthan those of group B at each time points. However the number of Baxpostive cells in group C and D were significantly lower than those of groupB at each time points.
Conclusions: Tetrandrine can prevent neurons from apoptosis andpromote the nerve function recover by inhibiting the expression of Bax and promoting the expression of Bcl-2.
PART TWO: EFFECT OF TETRANDRINE ON RELEASE OFINFLAMMATORY FACTOR FOLLOWING ACUTE SPINALCORD INJURY IN RATS
Objective:To observe the influence of tetrandrine on release ofinflammatory factor following spinal cord injury in rats.
Methods:78SD rats were randomly divided into:shamgroup,control group, Tet group.The modified Allen method was adopted tomake the models of T9spinal cord injury in control group and Tet group.The samples were taken from the spinal cord injury sites at6h,12h,1d,3d,5d,7ddetected the contents of TNF-α,IL-1β,IL-6,IL-10,NF-kBby using enzyme-linked immunosorbent assay.
Results: The expression of TNF-α, IL-1β, IL-6, IL-10, NF-kB ininjury control group and Tet group at6h,12h,1d,3d,5d,7d After ASCI washigher than that in sham operation group, has obviously increased at6hafter ASCI, peaked at24h-72h, began to decrease at5day after ASCI,.Theexpression of IL-10in Tet group was higher than the control group,but theexpression of TNF-α, IL-1β, IL-6, NF-kB is lower than the control group.
Conclusion:The content of TNF-α,IL-1β,IL-6,IL-10,NF-kB wasincrease in the spinal cord. Tetrandrine is able to improve local microenvironment and promote the nerve function recover by increasing theexpression of IL-10and decreasing the expression of TNF-α,IL-1 β,IL-6,NF-kB in the spinal cord injury.
PART THREE: EXPERIMENTAL STUDY ON EFFECT OFTETRANDRINE IN THE ENDOGENOUS NEURAL STEM CELLPROLIFERATION AND DIFFERENTIATION AFTER SPINALCORD INJURY IN RATS
Objective: Discuss the effects of tetrandrine on the endogenousneural stem cell proliferation and differentiation after spinal cord injury inrats.
Methods:78rats were randomly divided into3groups: injuriedgroup (n=36), Tet-treated group (n=36),sham-operated group (n=6).Injuried group and Tet-treated group damage spinal cord with Allen 'scombat modeling method.30minutes after damage, Tet was injected with adosage22.5mg/kg in Tet group at30minutes,24h and48h after ASCI, andthe same dosement of saline was injected in injuried group as control. Thesamples were dissected from the spinal cord injury sites at1d,3d,1w,2w,3w,4w and detected the expression of BrdU and nestin byimmunofluorescence staining.
Results: A little nestin positive cells and brdU positive cells werefound in injuried group and Tet-treated group at1day after injury. A largenumber of positive cells were found in both groups at one week after injuryand reached the peak which lasted for2weeks and then decreasedgradually. The expression of Nestin positive cells and brdU positive cells decreased significantly at4weeks after injury. Compared with the shamoperation group, the number of Nestin positive cells and brdU positive cellswas more in injuried group and Tet-treated group at1d,3d,1W,2W,3W afterinjury. The expression was higher in Tet-treated group than injuried groupat1d,3d,1w,2w,3w after injury and had no difference at4weeks afterinjury.
Conclusion: It was concluded that tetrandrine could increase thenumber of Nestin positive cells, brdU positive cells and endogenous neuralstem cells.It is beneficial to the recovery of spinal cord injury in rats.
引文
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