益气活血复方SXD抑制急性脑梗死炎性反应的实验研究
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摘要
目的 通过对脑缺血后炎性细胞因子TNF-α、外周血白细胞粘附分子CD_(11)／CD_(18)、细胞间粘附分子-1(ICAM-1)、核转录因子NF-κ B及caspase 3的变化，探讨益气活血中药复方SXD对急性脑梗死炎性反应和神经细胞凋亡的影响。
方法 电凝法闭塞大鼠大脑中动脉制成大脑中动脉闭塞(MCAO)模型。造模前8天开始灌胃，每天一次。模型动物随机分为SXD高剂量组、SXD中剂量组、SXD低剂量组、环磷酰胺组。选择假手术组、模型组、正常组作为对照。造模后继续灌胃并于造模后24、48、72小时三个不同时间点处死大鼠。HE染色观察梗死病理改变、尼氏染色观察尼氏体变化、TTC染色检测梗死体积、流式细胞术观察外周血白细胞CD_(11a)／CD_(18)、CD_(11b)／CD_(18)改变、RT-PCR检测TNF-α mRNA、ICAM-1mRNA表达、免疫组化观察NF-κ B、caspase 3阳性表达情况。
结果 SXD能缩小脑梗死体积，保护神经元；显著下调TNF-α mRNA的表达；显著降低外周血粘附分子CD_(11a)／CD_(18)、CD_(11b)／CD_(18)的表达和ICAM-1 mRNA的表达；抑制核转录因子NF-κ B的转录活性；上述变化高剂量SXD的作用强度与环磷酰胺相似，SXD部分指标不同剂量组之间呈现量效关系；SXD能显著抑制caspase 3的激活与表达，高剂量SXD抑制caspase 3表达的作用强于环磷酰胺。
不同剂量的SXD及一定剂量的环磷酰胺通过下调TNF-α mRNA的表达，抑制NF-κ B的激活与活性，降低ICAM-1mRNA和白细胞粘附分子CD_(11)／CD_(18)的表达，进而抑制ICAM-1与CD_(11)／CD_(18)的结合，抑制其介导的白细胞与血管内皮细胞之间的粘附，减轻炎性细胞的聚集与浸润，减轻缺血性脑损伤。另一方面，SXD与环磷酰胺通过下调TNF-α mRNA的表达，抑制了TNF-α诱导的脑缺血后细胞凋亡。同时还能直接抑制细胞凋亡的关键蛋白酶caspase 3，进而抑制脑缺血后神经细胞凋亡。
本研究运用有效成分组成益气活血复方SXD，从多层次、多角度系
统研究中药对急性脑梗死早期炎性反应的作用并初步证实其抗炎作用;首
次从基因表达水平研究了中药对脑缺血后炎性细胞因子TNF一Q的影响:
首次研究了中药对脑缺血损伤过程中NF一KB的作用;首次研究了中药对
脑缺血后影响神经细胞凋亡的关键蛋白酶caspase3的作用。在实验研究
基础上首次明确提出了抑制脑梗死后早期炎性反应可能是益气活血复方
及部分活血化癖中药治疗急性脑梗死的作用机理之一，这一观点需进一步
研究证实;首次提出脑缺血后出现的白细胞与内皮细胞粘附，炎性细胞聚
集、浸润，微血管堵塞也是中医“癖”的组织病理基础之一，丰富了中医
“癖”的内涵。
结论SXD能抑制M以O模型大鼠脑梗死早期的炎性反应，减轻脑缺血
后炎性病理损害;SXD能抑制神经细胞凋亡。
抑制脑梗死后早期炎性反应可能是益气活血复方及部分活血化癖中
药治疗急性脑梗死的作用机理之一;脑缺血后出现的白细胞与内皮细胞粘
附，炎性细胞聚集、浸润，微血管堵塞可能也是中医“痪”的组织病理基
础之一。
Objects: To investigate the effect of "tonifying qi and moving blood" formula on acute cerebral infarction inflammation response and apoptosis of nerve cell by detecting the changes of tumor necrosis factor- a , intercellular adhesion molecular-1(ICAM-1), nuclear factor k B(NF- k B),caspase3 in brain and leucocyte Adhesion molecule CD11/CD18 in blood after cerebral ischemia,
Methods: Electrocoagulation method to occlude middle cerebral artery of rat to make the MCAO rat model. Give SXD 8 days before making model, one time each day. MCAO rat model are dvided into 4 groups randomly as following: High dose SXD group; Middle dose SXD group; Low dose SXD group; Cyclophosphamide (Cytoxan) group. Sham operation group, Model group, and Normal group as control groups. After making model, the intervention period are 24 hours, 48 hours and 72 hours respectively. In this case, the infarct pathology alteration can be observed by noticing the change in HE, Nissl body change by Nissl's staining, infarct volume detected by TTC staining, CD11a/CD18,CD11b/CD18 in leucocyte detected by flow cytometry, expression of ICAM-lmRNA detected by RT-PCR, expression of NF- k Band caspase 3 tested by Immune histochemistry method.
Results: SXD have the function of decreasing the volume size of cerebral infarction and of protecting neuron. They can dramatically lower the expression of TNF-a m-RNA and that of adhesion molecular CD11a/CD18 CD11b/CD18 and ICAM-1 m-RNA, It also restrain the activation and expression of NF- k B. The function of the above high dose group is similar to the effect of Cytoxan. SXD and Cytoxan can decrease the expression of caspase3, and the effect of high dose SXD is better than Cytoxan group.
Deferent dosage SXD and stable dosage cyclophosphamide can control the
expression the integrate of ICAM-land CD11/CD18 and adhesiveness of leucocytes and blood vessel endothelial cell, can relieve the collection and infiltration of inflammation cell, can tissue infiltration and brain damage due to ischemia by regulate down the
expression of TNF- a mRNA, restrain the activation and activity of NF- k B, decrease the expression of ICAM-1mRNA and CD11/CD18. On the other hand, SXD and cyclophosphamide can restrain the apoptosis after cerebral ischemia by control the expression of TNF- a mRNA and caspase 3.
The experiments use active components of SXD to explore the herb function of inflammation in the early period of acute cerebral infarction, and, for the first time, prove the anti-inflammation role. We also research the influence on cytokine TNF- a after cerebral ischemia at gene level first. Further more, the experiments also include the influence on NF- k B during cerebral ischemia process and the influence on caspase 3, which is the key protease of apoptosis after cerebral ischemia. The experiments suggest that the anti-inflammation role after cerebral ischemia is an active mechanism of tonify qi and many move blood formula and part of move blood herb, which needs further confirmation. We are putting forward that the adhesiveness of leucocytes and endothelial cell, inflammation cell aggregation and infiltration, micro vessel blockage are among the basic pathological phenomena of "blood stasis" of traditional Chinese medicine; this hypothesis has certainly enriched the connotation of blood stasis of TCM
Conclusions: The results indicate that SXD can inhibit MCAO model rat inflammation response in early stage of infarct, decrease the pathological damage after cerebral ischemia, and restrain the apoptosis of nerve cell.
Anti-inflammation of cerebral infarction in early stage maybe one of the active
mechanism of tonify qi and move blood formula or part of move blood herbs. The adhesiveness of leucocytes and endothelial cell, the collection, infiltration of inflammation cell and blockage of micro vessel is one of pathology basis of "blood stasis" of TCM.
方法 电凝法闭塞大鼠大脑中动脉制成大脑中动脉闭塞(MCAO)模型。造模前8天开始灌胃，每天一次。模型动物随机分为SXD高剂量组、SXD中剂量组、SXD低剂量组、环磷酰胺组。选择假手术组、模型组、正常组作为对照。造模后继续灌胃并于造模后24、48、72小时三个不同时间点处死大鼠。HE染色观察梗死病理改变、尼氏染色观察尼氏体变化、TTC染色检测梗死体积、流式细胞术观察外周血白细胞CD_(11a)／CD_(18)、CD_(11b)／CD_(18)改变、RT-PCR检测TNF-α mRNA、ICAM-1mRNA表达、免疫组化观察NF-κ B、caspase 3阳性表达情况。
结果 SXD能缩小脑梗死体积，保护神经元；显著下调TNF-α mRNA的表达；显著降低外周血粘附分子CD_(11a)／CD_(18)、CD_(11b)／CD_(18)的表达和ICAM-1 mRNA的表达；抑制核转录因子NF-κ B的转录活性；上述变化高剂量SXD的作用强度与环磷酰胺相似，SXD部分指标不同剂量组之间呈现量效关系；SXD能显著抑制caspase 3的激活与表达，高剂量SXD抑制caspase 3表达的作用强于环磷酰胺。
不同剂量的SXD及一定剂量的环磷酰胺通过下调TNF-α mRNA的表达，抑制NF-κ B的激活与活性，降低ICAM-1mRNA和白细胞粘附分子CD_(11)／CD_(18)的表达，进而抑制ICAM-1与CD_(11)／CD_(18)的结合，抑制其介导的白细胞与血管内皮细胞之间的粘附，减轻炎性细胞的聚集与浸润，减轻缺血性脑损伤。另一方面，SXD与环磷酰胺通过下调TNF-α mRNA的表达，抑制了TNF-α诱导的脑缺血后细胞凋亡。同时还能直接抑制细胞凋亡的关键蛋白酶caspase 3，进而抑制脑缺血后神经细胞凋亡。
本研究运用有效成分组成益气活血复方SXD，从多层次、多角度系
统研究中药对急性脑梗死早期炎性反应的作用并初步证实其抗炎作用;首
次从基因表达水平研究了中药对脑缺血后炎性细胞因子TNF一Q的影响:
首次研究了中药对脑缺血损伤过程中NF一KB的作用;首次研究了中药对
脑缺血后影响神经细胞凋亡的关键蛋白酶caspase3的作用。在实验研究
基础上首次明确提出了抑制脑梗死后早期炎性反应可能是益气活血复方
及部分活血化癖中药治疗急性脑梗死的作用机理之一，这一观点需进一步
研究证实;首次提出脑缺血后出现的白细胞与内皮细胞粘附，炎性细胞聚
集、浸润，微血管堵塞也是中医“癖”的组织病理基础之一，丰富了中医
“癖”的内涵。
结论SXD能抑制M以O模型大鼠脑梗死早期的炎性反应，减轻脑缺血
后炎性病理损害;SXD能抑制神经细胞凋亡。
抑制脑梗死后早期炎性反应可能是益气活血复方及部分活血化癖中
药治疗急性脑梗死的作用机理之一;脑缺血后出现的白细胞与内皮细胞粘
附，炎性细胞聚集、浸润，微血管堵塞可能也是中医“痪”的组织病理基
础之一。
Objects: To investigate the effect of "tonifying qi and moving blood" formula on acute cerebral infarction inflammation response and apoptosis of nerve cell by detecting the changes of tumor necrosis factor- a , intercellular adhesion molecular-1(ICAM-1), nuclear factor k B(NF- k B),caspase3 in brain and leucocyte Adhesion molecule CD11/CD18 in blood after cerebral ischemia,
Methods: Electrocoagulation method to occlude middle cerebral artery of rat to make the MCAO rat model. Give SXD 8 days before making model, one time each day. MCAO rat model are dvided into 4 groups randomly as following: High dose SXD group; Middle dose SXD group; Low dose SXD group; Cyclophosphamide (Cytoxan) group. Sham operation group, Model group, and Normal group as control groups. After making model, the intervention period are 24 hours, 48 hours and 72 hours respectively. In this case, the infarct pathology alteration can be observed by noticing the change in HE, Nissl body change by Nissl's staining, infarct volume detected by TTC staining, CD11a/CD18,CD11b/CD18 in leucocyte detected by flow cytometry, expression of ICAM-lmRNA detected by RT-PCR, expression of NF- k Band caspase 3 tested by Immune histochemistry method.
Results: SXD have the function of decreasing the volume size of cerebral infarction and of protecting neuron. They can dramatically lower the expression of TNF-a m-RNA and that of adhesion molecular CD11a/CD18 CD11b/CD18 and ICAM-1 m-RNA, It also restrain the activation and expression of NF- k B. The function of the above high dose group is similar to the effect of Cytoxan. SXD and Cytoxan can decrease the expression of caspase3, and the effect of high dose SXD is better than Cytoxan group.
Deferent dosage SXD and stable dosage cyclophosphamide can control the
expression the integrate of ICAM-land CD11/CD18 and adhesiveness of leucocytes and blood vessel endothelial cell, can relieve the collection and infiltration of inflammation cell, can tissue infiltration and brain damage due to ischemia by regulate down the
expression of TNF- a mRNA, restrain the activation and activity of NF- k B, decrease the expression of ICAM-1mRNA and CD11/CD18. On the other hand, SXD and cyclophosphamide can restrain the apoptosis after cerebral ischemia by control the expression of TNF- a mRNA and caspase 3.
The experiments use active components of SXD to explore the herb function of inflammation in the early period of acute cerebral infarction, and, for the first time, prove the anti-inflammation role. We also research the influence on cytokine TNF- a after cerebral ischemia at gene level first. Further more, the experiments also include the influence on NF- k B during cerebral ischemia process and the influence on caspase 3, which is the key protease of apoptosis after cerebral ischemia. The experiments suggest that the anti-inflammation role after cerebral ischemia is an active mechanism of tonify qi and many move blood formula and part of move blood herb, which needs further confirmation. We are putting forward that the adhesiveness of leucocytes and endothelial cell, inflammation cell aggregation and infiltration, micro vessel blockage are among the basic pathological phenomena of "blood stasis" of traditional Chinese medicine; this hypothesis has certainly enriched the connotation of blood stasis of TCM
Conclusions: The results indicate that SXD can inhibit MCAO model rat inflammation response in early stage of infarct, decrease the pathological damage after cerebral ischemia, and restrain the apoptosis of nerve cell.
Anti-inflammation of cerebral infarction in early stage maybe one of the active
mechanism of tonify qi and move blood formula or part of move blood herbs. The adhesiveness of leucocytes and endothelial cell, the collection, infiltration of inflammation cell and blockage of micro vessel is one of pathology basis of "blood stasis" of TCM.
引文
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