MCAO气虚血瘀证大鼠子二代脑缺血耐受性及脂代谢情况的实验研究
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摘要
目的：
获取MCAO气虚血瘀证大鼠子二代,与正常同龄SD大鼠相比,研究其脑缺血耐受性有无差异,是否存在血脂紊乱及APOE基因表达的改变,探讨其缺血性脑卒中发病风险是否高于正常同龄SD大鼠。
方法：
第一部分：在获取的MCAO气虚血瘀证子二代大鼠中随机选取10只进行证候造模(模型组),与同样进行证候造模的10只正常同龄SD大鼠(对照组)及无干预因素参与的10只正常同龄SD大鼠(空白组)比较,观察其气虚证辨证评分、血瘀证辨证评分及相关行为学评分(旷场分析、攀网试验)
第二部分：随机选取前MCAO气虚血瘀证子二代大鼠20只及正常同龄SD大鼠20只,分为正常对照组、子二代组、药物干预组、假手术组4组,采用全脑一局灶脑缺血耐受的造模方法,观察其神经功能缺损评分,处死大鼠后,灌注固定脑组织,HE染色观察其缺血脑组织病理改变；免疫组化检测其缺血脑组织BDNF、Bax、Bel-2、ERK的表达。
第三部分：随机选取MCAO气虚血瘀证子二代大鼠10只(子二代组)及正常同龄SD大鼠10只(空白对照组),观察其血脂(TG、TC、HDL-C、LDL-C)及血浆APOE基因表达水平是否存在差异,并比较两组大鼠的血脂促动脉硬化指数及血脂综合指数。
结果：
第一部分：证候学评分：在证候造模因素干预前,模型组大鼠气虚证评分虽未达到8分,但明显高于对照组及空白组(P<0.05),而血瘀证的评分,在证候造模因素干预前三组大鼠无明显差异(P>0.05)；造模因素干预28天后,模型组10只大鼠中,有8只大鼠同时满足气虚证评分≥8分及血瘀证评分≥8分；而对照组10只大鼠中,仅有6只同时满足气虚证评分≥8分及血瘀证评分≥8分；且模型组气虚证评分与血瘀证评分均明显高于对照组。行为学评分：在证候造模因素干预前,模型组大鼠的中央格起始停留时间评分高于对照组和空白组,而模型组大鼠垂直活动次数评分低于对照组和空白组(P<0.05)；证候造模因素干预28天后,中央格起始停留时间评分,模型组明显高于对照组和空白组,且对照组也高于空白组,而大鼠垂直活动次数、跨格次数、攀网实验评分,模型组明显低于对照组和空白组,且对照组也低于空白组(P<0.05)。
第二部分：神经功能缺损评分：子二代组大鼠的神经功能损缺评分高于正常对照组(P<0.05),而与假手术组相比无明显差异(P>0.05)；同时药物干预组的神经功能损缺评分明显低于子二代组及假手术组(P<0.01)。BDNF表达：正常对照组、药物干预组的BDNF蛋白表达均高于假手术组及子二代组(P<0.05)；而子二代组的BDNF蛋白表达与假手术组相比,差异无统计学意义(P>0.05)。并且药物干预组的BDNF蛋白表达明显高于子二代组,差异有统计学意义(P<0.05)。Bax表达：正常对照组、药物干预组的Bax蛋白表达均低于假手术组及子二代组(P<0.05)：而子二代组的Bcl-2蛋白表达与假手术组相比,差异无统计学意义(P>0.05)。并且药物干预组的Bax蛋白表达明显低子二代组(P<0.05),而与正常对照组相比无明显差异(P>0.05)。Bcl-2表达：正常对照组、药物干预组的Bcl-2蛋白表达均高于假手术组子及二代组(P<0.05)；而子二代组的Bcl-2蛋白表达与假手术组相比,差异无统计学意义(P>0.05)。并且药物干预组的Bcl-2蛋白表达明显高于子二代组(P<0.05)。ERK表达：正常对照组、药物干预组的ERK蛋白表达均高于假手术组及子二代组(P<0.05)；而子二代组的ERK蛋白表达与假手术组相比,差异无统计学意义(P>0.05)。并且药物干预组的ERK蛋白表达明显高于子二代组(P<0.05)。
第三部分：血脂：子二代组大鼠的TC、LDL-C水平与空白对照组比较,无统计学差异(P>0.05)；而子二代组大鼠的TG水平明显高于空白对照组,(P<0.01),并且其HDL-C水平低于空白对照组(P<0.05)。子二代组大鼠的AIP及LCI均明显高于空白对照组(P<0.01)。血浆APOEmRNA表达：子二代组大鼠血浆中APOE基因表达的相对含量高于空白对照组(P<0.05)。
结论：
1. MCAO气虚血瘀证大鼠子二代与正常同龄SD大鼠相比,存在一定程度的气虚倾向,在证候造模因素的干预下,能更为容易的形成更加明显的气虚血瘀证候；
2. MCAO气虚血瘀证大鼠子二代与正常同龄SD大鼠相比,对脑缺血的耐受及修复能力降低,在缺血因素的干预下更容易形成更严重的缺血性脑损害,其发生缺血性脑卒中的风险高于正常同龄SD大鼠。
3. MCAO气虚血瘀证子二代大鼠的脑缺血耐受性降低可能与其ERK信号转导通路及其下游靶基因和蛋白(细胞凋亡相关基因Bcl-2、Bax, BDNF)的表达异常有关。
4.使用益气活血的脑心通胶囊可以改善MCAO气虚血瘀证子二代大鼠的脑缺血耐受性,促进其对缺血性脑损伤的修复能力。
5. MCAO气虚血瘀证大鼠子二代与正常同龄SD大鼠相比,存在明确的血脂代谢紊乱。
6. MCAO气虚血瘀证大鼠子二代与正常同龄SD大鼠相比,血浆APOEmRNA表达增高。
Objective:
To study whether there are any differences on the ischemic tolerance between the second filial generation (F2) of the middle cerebral artery occlusion (MCAO) model rats with blood-stasis-due-to-qi-deficiency syndrome (BSDTQDS) and the normally contemporary SD rats. And next to observe whether there were metabolic disorder of blood lipid in the F2 of MCAO- model rats with BSDTQDS, and whether the expression of APOE in plasma of the F2 of MCAO- model rats with BSDTQDS were significantly difference with the normally contemporary SD rats. To Research whether there are more risk factors in ischemic stroke in the second generation of MCAO- model rats with BSDTQDS than normally contemporary rats.
Method:
Part 1:The F2 rats were born through the First filial generation (F,) rats which were born through mating between male/female SD rats after BSDTQD syndrome molding and MCAO apoplexy molding, and such subjects were made syndrome molding once again to produce 10 second generation of syndrome experimental group(SEG) and compared with 10 normally contemporary SD rats by the same syndrome molding in syndrome controlled group(SCG) and other 10 normally contemporary SD rats without any intervention involved in blank controlled group(BCG) to compare changes in qi-deficiency syndrome grading, blood-stasis syndrome grading and related ethology index like open-field test, net-climbing.
Part 2:In this part, ischemic preconditioning (IP) was induced by ligation of dual common carotid artery 3 min. Middle cerebral artery occlusion (MCAO) was induced by intraluminal filament for 2h after IP 3d. drug intervention was induced by Naoxintong administration through esophagus once a day. sham operation group was induced by Pretreatment Of sham Surgery.20 the F2 of MCAO- model rats with BSDTQDS and 20 SD rats were included and randomly divided in to 4 groups:normally group (normally +IP+MCAO). the F2 group (F2+IP+MCAO). drug intervention group (F2 +drug-treated+IP+MCAO). sham operation group (SS+MCAO). At 22h perfusion end Point, the neurologic deficit score, histopathological changes with HE staining and the expression of BDNF、Bax、Bcl-2 and ERK by using immunohistochemistry method were evaluated in each group.
Part 3:The rats were divided into two groups randomly:model group (10 the F2 of MCAO- model rats), normal group (10 normally contemporary SD rats). The two group rats without any intervention were took the blood to do examinations as follow:①the levels of triglyceride(TG)、total cholesterol (TC)、high density lipoprotein cholesterol (HDL-c)、low density lipoprotein cholesterol(LDL-c) in blood.②analyze the atherogenic index of plasma (AIP) and Lipid Comprehensive index (LCI).③the expression of Apolipoprotein E (APOE) in plasma were examined by real-time reverse transcription-polymerase chain reaction.
Result:
Part1:Before being molded, qi-deficiency syndrome grading and related ethology index of SEG showed statistically significant difference in comparison with others, meanwhile blood-stasis syndrome grading showed no statistically significant difference among them. Having being molded, qi-deficiency syndrome grading, blood-stasis syndrome grading and related ethology index of SEG showed statistically significant difference in comparison with others.
Part2:the neurologic deficit scores of the F2 +IP+MCAO group were significantly higher than that of the normally +IP+MCAO group and the F2 + drug -treated +IP+MCAO group. Meanwhile the expression of BDNF、Bcl-2 and ERK in the ischemic brain tissue of of the F2+IP+MCAO group were significantly less than that of the normally +IP+MCAO group and the F2+ drug -treated +IP+MCAO group, and the expression of Bax in the ischemic brain tissue of the F2 +IP+MCAO group were significantly higher than that of the normally +IP+MCAO group and the F2+drug -treated +IP+MCAO group.
Part3:There were statistically significant difference in the levels of blood lipid(TG、TC、HDL-c、LDL-c)and the expression of APOE in plasma between the F2 of MCAO- model rats and the normally contemporary SD rats. Meanwhile, the atherogenic index of plasma and Lipid Comprehensive index of the F2 of MCAO- model rats were significantly higher than the normally contemporary SD rats.
Conclusion:
1. The trend of qi-deficiency syndrome at the F2 of MCAO- model rats with BSDTQDS are more than that of the normally contemporary SD rats. What's more, the F2of MCAO- model rats with BSDTQDS could be likely led by molding of BSDTQDS to more serious BSDTQDS manifestations than normally contemporary SD rats.
2. Comparing with the the normally contemporary SD rats, the ischemic tolerance of the F2 of MCAO- model rats with BSDTQDS were reduced, and the risk of ischemic were increased.
3. ERK signal transduction pathway and the expression of it's downstream target genes (such as BDNF、Bax and Bcl-2)might play important role in induction of the change of the ischemic tolerance in the F2 of MCAO- model rats with BSDTQDS.
4. Naoxintong can improve the the ischemic tolerance of the F2 of MCAO-model rats with BSDTQDS.
5. There were metabolic disorder of blood lipid in the F2 of MCAO- model rats with BSDTQDS.
6. The expression of APOE in plasma of the F2 of MCAO- model rats with BSDTQDS were significantly higher than that of the normally contemporary SD rats.
获取MCAO气虚血瘀证大鼠子二代,与正常同龄SD大鼠相比,研究其脑缺血耐受性有无差异,是否存在血脂紊乱及APOE基因表达的改变,探讨其缺血性脑卒中发病风险是否高于正常同龄SD大鼠。
方法：
第一部分：在获取的MCAO气虚血瘀证子二代大鼠中随机选取10只进行证候造模(模型组),与同样进行证候造模的10只正常同龄SD大鼠(对照组)及无干预因素参与的10只正常同龄SD大鼠(空白组)比较,观察其气虚证辨证评分、血瘀证辨证评分及相关行为学评分(旷场分析、攀网试验)
第二部分：随机选取前MCAO气虚血瘀证子二代大鼠20只及正常同龄SD大鼠20只,分为正常对照组、子二代组、药物干预组、假手术组4组,采用全脑一局灶脑缺血耐受的造模方法,观察其神经功能缺损评分,处死大鼠后,灌注固定脑组织,HE染色观察其缺血脑组织病理改变；免疫组化检测其缺血脑组织BDNF、Bax、Bel-2、ERK的表达。
第三部分：随机选取MCAO气虚血瘀证子二代大鼠10只(子二代组)及正常同龄SD大鼠10只(空白对照组),观察其血脂(TG、TC、HDL-C、LDL-C)及血浆APOE基因表达水平是否存在差异,并比较两组大鼠的血脂促动脉硬化指数及血脂综合指数。
结果：
第一部分：证候学评分：在证候造模因素干预前,模型组大鼠气虚证评分虽未达到8分,但明显高于对照组及空白组(P<0.05),而血瘀证的评分,在证候造模因素干预前三组大鼠无明显差异(P>0.05)；造模因素干预28天后,模型组10只大鼠中,有8只大鼠同时满足气虚证评分≥8分及血瘀证评分≥8分；而对照组10只大鼠中,仅有6只同时满足气虚证评分≥8分及血瘀证评分≥8分；且模型组气虚证评分与血瘀证评分均明显高于对照组。行为学评分：在证候造模因素干预前,模型组大鼠的中央格起始停留时间评分高于对照组和空白组,而模型组大鼠垂直活动次数评分低于对照组和空白组(P<0.05)；证候造模因素干预28天后,中央格起始停留时间评分,模型组明显高于对照组和空白组,且对照组也高于空白组,而大鼠垂直活动次数、跨格次数、攀网实验评分,模型组明显低于对照组和空白组,且对照组也低于空白组(P<0.05)。
第二部分：神经功能缺损评分：子二代组大鼠的神经功能损缺评分高于正常对照组(P<0.05),而与假手术组相比无明显差异(P>0.05)；同时药物干预组的神经功能损缺评分明显低于子二代组及假手术组(P<0.01)。BDNF表达：正常对照组、药物干预组的BDNF蛋白表达均高于假手术组及子二代组(P<0.05)；而子二代组的BDNF蛋白表达与假手术组相比,差异无统计学意义(P>0.05)。并且药物干预组的BDNF蛋白表达明显高于子二代组,差异有统计学意义(P<0.05)。Bax表达：正常对照组、药物干预组的Bax蛋白表达均低于假手术组及子二代组(P<0.05)：而子二代组的Bcl-2蛋白表达与假手术组相比,差异无统计学意义(P>0.05)。并且药物干预组的Bax蛋白表达明显低子二代组(P<0.05),而与正常对照组相比无明显差异(P>0.05)。Bcl-2表达：正常对照组、药物干预组的Bcl-2蛋白表达均高于假手术组子及二代组(P<0.05)；而子二代组的Bcl-2蛋白表达与假手术组相比,差异无统计学意义(P>0.05)。并且药物干预组的Bcl-2蛋白表达明显高于子二代组(P<0.05)。ERK表达：正常对照组、药物干预组的ERK蛋白表达均高于假手术组及子二代组(P<0.05)；而子二代组的ERK蛋白表达与假手术组相比,差异无统计学意义(P>0.05)。并且药物干预组的ERK蛋白表达明显高于子二代组(P<0.05)。
第三部分：血脂：子二代组大鼠的TC、LDL-C水平与空白对照组比较,无统计学差异(P>0.05)；而子二代组大鼠的TG水平明显高于空白对照组,(P<0.01),并且其HDL-C水平低于空白对照组(P<0.05)。子二代组大鼠的AIP及LCI均明显高于空白对照组(P<0.01)。血浆APOEmRNA表达：子二代组大鼠血浆中APOE基因表达的相对含量高于空白对照组(P<0.05)。
结论：
1. MCAO气虚血瘀证大鼠子二代与正常同龄SD大鼠相比,存在一定程度的气虚倾向,在证候造模因素的干预下,能更为容易的形成更加明显的气虚血瘀证候；
2. MCAO气虚血瘀证大鼠子二代与正常同龄SD大鼠相比,对脑缺血的耐受及修复能力降低,在缺血因素的干预下更容易形成更严重的缺血性脑损害,其发生缺血性脑卒中的风险高于正常同龄SD大鼠。
3. MCAO气虚血瘀证子二代大鼠的脑缺血耐受性降低可能与其ERK信号转导通路及其下游靶基因和蛋白(细胞凋亡相关基因Bcl-2、Bax, BDNF)的表达异常有关。
4.使用益气活血的脑心通胶囊可以改善MCAO气虚血瘀证子二代大鼠的脑缺血耐受性,促进其对缺血性脑损伤的修复能力。
5. MCAO气虚血瘀证大鼠子二代与正常同龄SD大鼠相比,存在明确的血脂代谢紊乱。
6. MCAO气虚血瘀证大鼠子二代与正常同龄SD大鼠相比,血浆APOEmRNA表达增高。
Objective:
To study whether there are any differences on the ischemic tolerance between the second filial generation (F2) of the middle cerebral artery occlusion (MCAO) model rats with blood-stasis-due-to-qi-deficiency syndrome (BSDTQDS) and the normally contemporary SD rats. And next to observe whether there were metabolic disorder of blood lipid in the F2 of MCAO- model rats with BSDTQDS, and whether the expression of APOE in plasma of the F2 of MCAO- model rats with BSDTQDS were significantly difference with the normally contemporary SD rats. To Research whether there are more risk factors in ischemic stroke in the second generation of MCAO- model rats with BSDTQDS than normally contemporary rats.
Method:
Part 1:The F2 rats were born through the First filial generation (F,) rats which were born through mating between male/female SD rats after BSDTQD syndrome molding and MCAO apoplexy molding, and such subjects were made syndrome molding once again to produce 10 second generation of syndrome experimental group(SEG) and compared with 10 normally contemporary SD rats by the same syndrome molding in syndrome controlled group(SCG) and other 10 normally contemporary SD rats without any intervention involved in blank controlled group(BCG) to compare changes in qi-deficiency syndrome grading, blood-stasis syndrome grading and related ethology index like open-field test, net-climbing.
Part 2:In this part, ischemic preconditioning (IP) was induced by ligation of dual common carotid artery 3 min. Middle cerebral artery occlusion (MCAO) was induced by intraluminal filament for 2h after IP 3d. drug intervention was induced by Naoxintong administration through esophagus once a day. sham operation group was induced by Pretreatment Of sham Surgery.20 the F2 of MCAO- model rats with BSDTQDS and 20 SD rats were included and randomly divided in to 4 groups:normally group (normally +IP+MCAO). the F2 group (F2+IP+MCAO). drug intervention group (F2 +drug-treated+IP+MCAO). sham operation group (SS+MCAO). At 22h perfusion end Point, the neurologic deficit score, histopathological changes with HE staining and the expression of BDNF、Bax、Bcl-2 and ERK by using immunohistochemistry method were evaluated in each group.
Part 3:The rats were divided into two groups randomly:model group (10 the F2 of MCAO- model rats), normal group (10 normally contemporary SD rats). The two group rats without any intervention were took the blood to do examinations as follow:①the levels of triglyceride(TG)、total cholesterol (TC)、high density lipoprotein cholesterol (HDL-c)、low density lipoprotein cholesterol(LDL-c) in blood.②analyze the atherogenic index of plasma (AIP) and Lipid Comprehensive index (LCI).③the expression of Apolipoprotein E (APOE) in plasma were examined by real-time reverse transcription-polymerase chain reaction.
Result:
Part1:Before being molded, qi-deficiency syndrome grading and related ethology index of SEG showed statistically significant difference in comparison with others, meanwhile blood-stasis syndrome grading showed no statistically significant difference among them. Having being molded, qi-deficiency syndrome grading, blood-stasis syndrome grading and related ethology index of SEG showed statistically significant difference in comparison with others.
Part2:the neurologic deficit scores of the F2 +IP+MCAO group were significantly higher than that of the normally +IP+MCAO group and the F2 + drug -treated +IP+MCAO group. Meanwhile the expression of BDNF、Bcl-2 and ERK in the ischemic brain tissue of of the F2+IP+MCAO group were significantly less than that of the normally +IP+MCAO group and the F2+ drug -treated +IP+MCAO group, and the expression of Bax in the ischemic brain tissue of the F2 +IP+MCAO group were significantly higher than that of the normally +IP+MCAO group and the F2+drug -treated +IP+MCAO group.
Part3:There were statistically significant difference in the levels of blood lipid(TG、TC、HDL-c、LDL-c)and the expression of APOE in plasma between the F2 of MCAO- model rats and the normally contemporary SD rats. Meanwhile, the atherogenic index of plasma and Lipid Comprehensive index of the F2 of MCAO- model rats were significantly higher than the normally contemporary SD rats.
Conclusion:
1. The trend of qi-deficiency syndrome at the F2 of MCAO- model rats with BSDTQDS are more than that of the normally contemporary SD rats. What's more, the F2of MCAO- model rats with BSDTQDS could be likely led by molding of BSDTQDS to more serious BSDTQDS manifestations than normally contemporary SD rats.
2. Comparing with the the normally contemporary SD rats, the ischemic tolerance of the F2 of MCAO- model rats with BSDTQDS were reduced, and the risk of ischemic were increased.
3. ERK signal transduction pathway and the expression of it's downstream target genes (such as BDNF、Bax and Bcl-2)might play important role in induction of the change of the ischemic tolerance in the F2 of MCAO- model rats with BSDTQDS.
4. Naoxintong can improve the the ischemic tolerance of the F2 of MCAO-model rats with BSDTQDS.
5. There were metabolic disorder of blood lipid in the F2 of MCAO- model rats with BSDTQDS.
6. The expression of APOE in plasma of the F2 of MCAO- model rats with BSDTQDS were significantly higher than that of the normally contemporary SD rats.
引文
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