眼针促进局灶性脑缺血大鼠血管新生和抑制炎症反应的研究
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摘要
目的：脑卒中是指急性起病，由于脑局部血液循环障碍所导致的神经功能缺损综合征，其发病率、死亡率及致残率均高，是目前导致人类死亡的第2位原因，随着人口老龄化的趋势，脑卒中的发病率逐年上升，严重危害人类的健康。脑卒中临床上分缺血性和出血性脑卒中两大类，其中缺血性卒中的发病率占3/4。缺血性脑卒中的治疗方法主要有两种，血管重构和神经保护（阻断半暗带神经细胞死亡的级联反应）。围绕这两种机制进行的药物开发临床疗效不理想，因此如何防治缺血性脑卒中一直是医学界面临的难题。
缺血性脑血管病中医属于“中风”范畴，为本虚标实之症，其本为肝肾阴虚，其标为风、痰、火、瘀阻于脑络所致。中风的急性期为邪气实、正气虚同时存在，故中风急性期的治疗原则为“扶正祛邪”并重。眼针属于针灸的一种方式，其治疗中风病已有四十多年，临床取其较好疗效。然而，眼针治疗中风的机制尚不明确，使这种治疗方式推广受限。脑缺血缺氧后可以引发炎症的过度反应，损害神经元，也可以诱发代偿性的血管新生，保护神经元。抑制炎症反应和促进血管新生两种治疗方式与中医治疗原则“扶正祛邪”相符，眼针治疗缺血性脑血管病是否与这两种机制有关？本课题从抑制炎症因子和促血管新生角度研究眼针对急性缺血性脑血管病损伤的保护机制，证实眼针治疗缺血性脑血管病是多途径、多靶点的，为临床治疗提供理论依据。
材料与方法：
将SPF级SD大鼠80只随机分为空白组、假手术组、模型组、眼针组，除空白组外其余三组再按脑缺血2h再灌注3h、24h、72h分为3个亚组，共10组，每组8只。空白组不予处理，正常给水给食，采用改良线栓法制备局灶性脑缺血再灌注模型，假手术组处理方式与模型组相同，不同在于线栓仅插入5㎜，眼针刺激“肝区”、“肾区”、“上焦”、“下焦”穴位，于脑缺血再灌注即刻行第1次眼针刺激，动物存活期间每隔12h进行眼针治疗1次。运用行为观察法检测大鼠神经功能缺损评分；运用免疫组织化学法检测各组大鼠缺血侧大脑微血管密度、核转录因子、神经细胞间黏附因子、内皮细胞生长因子及其受体蛋白表达的变化；双抗夹心法检测血清乏氧诱导因子含量；RT-PCR法检测大鼠各组缺血侧内皮细胞生长因子及其受体的变化，并进一步分析各指标时空变化规律及眼针的干预作用。
结果：
⑴模型组大鼠神经功能缺损评分再灌注后加重，缺损严重程度在24h达到高峰，72h开始下降；眼针组大鼠神经功能缺损评分再灌注3h开始下降，随时间延长进一步下降；眼针组与模型组比，在灌注后3h症状有所减轻，但评分无统计学差异（P>0.05）；再灌注后24h、72h，症状明显减轻，评分有显著差异（P<0.05）。提示，眼针治疗可以改善局灶性脑缺血大鼠神经功能障碍。
⑵空白组与假手术组可见微量NF-κBp65、VCAM-1蛋白表达，且棕黄色表达位于胞浆中。模型组NF-κBp65、VCAM-1免疫染色于再灌注3h开始增强，24h达到高峰，72h表达开始下降，棕黄色表达多位于细胞核中；眼针组与模型组表达趋势相同，各时间点与模型组比显著降低（P<0.05）。提示：眼针可以抑制炎症因子表达，发挥脑保护作用。
⑶空白组与假手术组末见CD34阳性表达的微血管密度。模型组CD34微血管阳性表达在再灌注24h迅速上升，持续升高至再灌注72h。棕黄色表达在缺血坏死区周围皮层明显增多，眼针组与模型组表达规律一致，表达更广泛，各时间点有显著差异（P<0.05）。提示：眼针治疗可以促进脑缺血后的血管新生。
⑷空白组与假手术组血清HIF-1α含量少量表达；模型组血清中HIF-1α含量在再灌注3h明显上调，持续至72h开始下降，但仍高于正常水平，在再灌注24h达到高峰；眼针组与模型组表达规律一致，但眼针组升高更显著，与模型组比各时间点有显著差异（P<0.05）。提示：眼针可以通过提高HIF-1α的蛋白表达，发挥脑保护作用。
⑸空白组与假手术组VEGF及其受体VEGFR-2基因及蛋白表达微量；模型组VEGF及其受体VEGFR-2基因及蛋白于再灌注3h表达明显增强，随时间延长，表达进一步增加，持续至72h仍处于较高水平；经眼针治疗后，眼针组的VEGF、VEGFR-2基因及蛋白表达明显升高，与同时间点的模型组比有显著差异（P<0.05）。提示：眼针可以促进VEGF/VEGFR系统的表达，发挥脑保护作用
结论：
早期眼针介入能较有效地改善大鼠脑缺血后的神经功能缺损评分，随针刺的时间延长，其神经功能恢复程度提高。通过CD34阳性标记，眼针刺激后缺血区周围微血管计数比模型组明显增多，表明眼针治疗缺血性脑血管病的机制之一是促进了缺血再灌注后的新血管形成。
脑缺血再灌注可以诱导HIF-1α、VEGF、VEGFR-2的表达，其表达代偿性增加，提示它们参与了脑缺血再灌注的级联反应，在脑损伤的修复过程中起到保护作用。而眼针激活内源性血管新生机制，与上调HIF-1α、VEGF、VEGFR-2表达有关。通过进一步分析各组缺血侧HIF-1α、VEGF、VEGFR-2表达的时间规律，认为在脑缺血再灌注早期眼针通过激活HIF-VEGF/VEGFR-2通路促进血管新生。此外，眼针可能通过抑制NF-κBp65、VCAM-1等炎症因子来减轻缺血区细胞损伤；多方面效应协同作用，有效减轻了脑缺血再灌注大鼠神经行为学障碍，发挥对抗缺血性脑损伤作用。
Purpose：Stroke, also known as emergent disease, is a neurologicimpairment syndrome, because of cerebral blood circulation disorder. Due to it′s the high level of incidence, death and disability, stroke has emerged asthe second causes of mortality in the human. With the numbers of the elderlyare raised, the incidence of stroke is rise every year, which is regarded asserious threat to human health. Stroke can be classified into two majorcategories: ischemic and hemorrhagic, about3/4of strokes are caused by ischemia.It′s two major way to therapy this disease is: the formation of new blood vesselsand neurprotection (block penumbra neuron death cascade reaction).The new drugs,whose mechanism therapy ischemia were about that,were little effective in clinic.So that how to treat and prevent ischemia is always the challenges faced by themedical..
Ischemic is belong to “ZhongFeng” in traditional chanise medical,and itssymptoms are asthenia in the root and sthenia in the branch. Its root is astheniaof liver yin and kidney yin, and its branch is wind, phlegm fire and stagnationwhich block channels and collaterals of brain. During period of acutely ZhongFeng there are excess of pathogenic factors and deficiency of healthy qi. Sothat principle of treatment to acute Zhong Feng is strengthening heathy qi andeliminate pathogenic factors. Eye acupuncture is belong to acupuncture. But themechanism of eye acupuncture therapy ischemia is obscure, that limit this therapywere used furthermore. There are induced inflammatory reaction excess afterbrain hypoxia, that can damage neuron. In addition that might inducedcompensatory angiogenesis, that can protect neuron. This two therapy-reduceinflammatory and improve angiogenesis, assemebly as. Wethere is the mechanismof eye acupuncture therapy ischemia related that? We reveal the protectedmechanism of action of eye acupuncture therapy to acute ischemia through reducinginflammatory and improving angiogenesis, that proved eye acupuncture therapy ischemia is targets and ways, and provide theory base to clinic therapy.
Material and method：To80SD rats were randomly divided into blank group,sham operation group model group eye acupuncture group. Its were divided intothree sub-group according to2hour′ischemia following by reperfusion by3h24h72h respectively, excluding black group, that plus a total of ten group,every group have eight. The black group was not treated and supplied normal waterand food. the rat model of cerebral ischemia-reperfusion injury was establishedby suture method. sham operation group model was established alike the modelgroup, its difference is suture poll into0.5mm.. The1st eye acupuncture therapyafter reperfusion at“Kindy”,Vindy”,”Sangjiao”,”Xiajiao”points. Andthen the eye acupuncture the eye acupuncture therapy in every12h, until ratsdie. Detection of use of behavioral observations of rats in each group scoreof neurological symptoms; immunohistochemical techniques were employed todetect the microvessel density,the protein expression of NF-KBp65,VCAM-1,VEGFand Flt-1; RT-PCR techniques were employed to detect the expression VEGF/Flt-1HIF-1mRNA; ELASA techniques were employed to detect HIF-1αof serum; Wester blottechniques were employed to detect the protein expression of HIF-1α.And furtherto analyse the indicators of spatial and temporal changes in the law and theeffects of eye acupuncture intervention.
Results：
⑴Model group rat′neurological deficit score is raising to24h afterreperfusion, which is begin to decreased at72h after reperfusion. Eyeacupuncture group′nerve missing sign of rats are improving from3h to72h, whosescores were significantly different from the model ones at24h72h.Eyeacupuncture could effectively neurological deficit score after ischemic ratbrain
⑵In ischemia2h reperfusion3h,the little protein expression of NF-κBp65andVCAM-1in the blank group and sham operation group model group; the immunestaining of NF-κBp65and VCAM-1enhanced, the cytoplasm showed brown which reached the peak in24h after reperfusion and reduced at72h. The expressionof NF-κBp65and VCAM-1were basically same between eye acupuncture group andmodel group, but the eye acupuncture one was less. After treatment of eyeacupuncture, compared to the same period of the model group, the immune stainingof NF-κBp65and VCAM-1of the eye acupuncture group were significantlydifferention. Eye acupuncture could protect brain through inhibitedinflammatory
⑶There are not expression of CD34in the blank group and sham operation groupmodel group;Model group, the expression of CD34microvascular increase rapidlyat24h after reperfusion, and sustainly to72h reperfusion. The expression ofCD34around necrosis of cerebral cortex was increased significantly. Theexpression of CD34was basically same between eye acupuncture group and modelgroup,but the eye acupuncture one was more. eye acupuncture group compared withthe model group were significantly different from reperfusion at different timepoints.This prove eye acupuncture access angiogenges after ischemic.
⑷There are little of HIF-1αin the blank group and sham operation group modelgroup; In serum the of HIF-1α in rat brain increase rapidly at3h afterreperfusion, and which begin decrease until72h reperfusion. the pick of HIF-1αat24h. The expression of HIF-1α was basically same between eye acupuncturegroup and model group, but eye acupuncture group can promote the expression ofHIF-1α,compared with the model group were significantly different fromreperfusion at different time points. Eye acupuncture could protect brainthrough raised HIF-1α
⑸There are little the protein and gene expression of VEGF and its receptorFlk-1were in the blank group and sham operation group model group the proteinand gene expression of VEGF and its receptor Flk-1were rise raptly3h afterreperfusion, which increase sustainly with time reperfusion largely, thatcontinued to72h. After eye acupuncture therapy,the expression of VEGF and Flk-1could promote, which are higher than the corresponding phase of model group,there were significant differences between the two groups. Eye acupuncture could protect brain through improved VEGF/VEGFR
Conclusion：
Eye acupuncture can improve effectively neurological deficit score afterischemic rat brain early, and further promote its recovery of neurologicalfunction with increase eye acupuncture therapy. By the CD34marker, themicrovessel count of eye acupuncture in ischemic areas was more significantlyincreased than the model, indicating that one of mechanism how eye acupuncturetherapy cerebral ischemia is to promote the formation of new blood vessels afterischemia-reperfusion.
Cerebral ischemia-reperfusion can induce the expression of HIF-1α, VEGFand Flk-1. Compensatory increasing in its expression suggested that theyinvolved cascade of ischemia-reperfusion, and make significant role ofprotection in the healing process of the brain injury. eye acupuncture can activemechanism of endogenous angiogenesis, which related to the increase of theexpression of HIF-1α, VEGF and Flk-1. In early ischemia-reperfusion, eyeacupuncture can active HIF-VEGF pathway to promote angiogenesis, through furtheranalysis the indicators of spatial and temporal changes in the law. In addition,eye acupuncture can reduce inflammation like as: NF-κBp65、VCAM-1, so that whichmight reduce damage of ischemic cell. These effects of eye acupuncture mightcorporately reduce neurobehavioral disorders in rate with ischemia-reperfusion,providing effective protective to ischemia.
缺血性脑血管病中医属于“中风”范畴，为本虚标实之症，其本为肝肾阴虚，其标为风、痰、火、瘀阻于脑络所致。中风的急性期为邪气实、正气虚同时存在，故中风急性期的治疗原则为“扶正祛邪”并重。眼针属于针灸的一种方式，其治疗中风病已有四十多年，临床取其较好疗效。然而，眼针治疗中风的机制尚不明确，使这种治疗方式推广受限。脑缺血缺氧后可以引发炎症的过度反应，损害神经元，也可以诱发代偿性的血管新生，保护神经元。抑制炎症反应和促进血管新生两种治疗方式与中医治疗原则“扶正祛邪”相符，眼针治疗缺血性脑血管病是否与这两种机制有关？本课题从抑制炎症因子和促血管新生角度研究眼针对急性缺血性脑血管病损伤的保护机制，证实眼针治疗缺血性脑血管病是多途径、多靶点的，为临床治疗提供理论依据。
材料与方法：
将SPF级SD大鼠80只随机分为空白组、假手术组、模型组、眼针组，除空白组外其余三组再按脑缺血2h再灌注3h、24h、72h分为3个亚组，共10组，每组8只。空白组不予处理，正常给水给食，采用改良线栓法制备局灶性脑缺血再灌注模型，假手术组处理方式与模型组相同，不同在于线栓仅插入5㎜，眼针刺激“肝区”、“肾区”、“上焦”、“下焦”穴位，于脑缺血再灌注即刻行第1次眼针刺激，动物存活期间每隔12h进行眼针治疗1次。运用行为观察法检测大鼠神经功能缺损评分；运用免疫组织化学法检测各组大鼠缺血侧大脑微血管密度、核转录因子、神经细胞间黏附因子、内皮细胞生长因子及其受体蛋白表达的变化；双抗夹心法检测血清乏氧诱导因子含量；RT-PCR法检测大鼠各组缺血侧内皮细胞生长因子及其受体的变化，并进一步分析各指标时空变化规律及眼针的干预作用。
结果：
⑴模型组大鼠神经功能缺损评分再灌注后加重，缺损严重程度在24h达到高峰，72h开始下降；眼针组大鼠神经功能缺损评分再灌注3h开始下降，随时间延长进一步下降；眼针组与模型组比，在灌注后3h症状有所减轻，但评分无统计学差异（P>0.05）；再灌注后24h、72h，症状明显减轻，评分有显著差异（P<0.05）。提示，眼针治疗可以改善局灶性脑缺血大鼠神经功能障碍。
⑵空白组与假手术组可见微量NF-κBp65、VCAM-1蛋白表达，且棕黄色表达位于胞浆中。模型组NF-κBp65、VCAM-1免疫染色于再灌注3h开始增强，24h达到高峰，72h表达开始下降，棕黄色表达多位于细胞核中；眼针组与模型组表达趋势相同，各时间点与模型组比显著降低（P<0.05）。提示：眼针可以抑制炎症因子表达，发挥脑保护作用。
⑶空白组与假手术组末见CD34阳性表达的微血管密度。模型组CD34微血管阳性表达在再灌注24h迅速上升，持续升高至再灌注72h。棕黄色表达在缺血坏死区周围皮层明显增多，眼针组与模型组表达规律一致，表达更广泛，各时间点有显著差异（P<0.05）。提示：眼针治疗可以促进脑缺血后的血管新生。
⑷空白组与假手术组血清HIF-1α含量少量表达；模型组血清中HIF-1α含量在再灌注3h明显上调，持续至72h开始下降，但仍高于正常水平，在再灌注24h达到高峰；眼针组与模型组表达规律一致，但眼针组升高更显著，与模型组比各时间点有显著差异（P<0.05）。提示：眼针可以通过提高HIF-1α的蛋白表达，发挥脑保护作用。
⑸空白组与假手术组VEGF及其受体VEGFR-2基因及蛋白表达微量；模型组VEGF及其受体VEGFR-2基因及蛋白于再灌注3h表达明显增强，随时间延长，表达进一步增加，持续至72h仍处于较高水平；经眼针治疗后，眼针组的VEGF、VEGFR-2基因及蛋白表达明显升高，与同时间点的模型组比有显著差异（P<0.05）。提示：眼针可以促进VEGF/VEGFR系统的表达，发挥脑保护作用
结论：
早期眼针介入能较有效地改善大鼠脑缺血后的神经功能缺损评分，随针刺的时间延长，其神经功能恢复程度提高。通过CD34阳性标记，眼针刺激后缺血区周围微血管计数比模型组明显增多，表明眼针治疗缺血性脑血管病的机制之一是促进了缺血再灌注后的新血管形成。
脑缺血再灌注可以诱导HIF-1α、VEGF、VEGFR-2的表达，其表达代偿性增加，提示它们参与了脑缺血再灌注的级联反应，在脑损伤的修复过程中起到保护作用。而眼针激活内源性血管新生机制，与上调HIF-1α、VEGF、VEGFR-2表达有关。通过进一步分析各组缺血侧HIF-1α、VEGF、VEGFR-2表达的时间规律，认为在脑缺血再灌注早期眼针通过激活HIF-VEGF/VEGFR-2通路促进血管新生。此外，眼针可能通过抑制NF-κBp65、VCAM-1等炎症因子来减轻缺血区细胞损伤；多方面效应协同作用，有效减轻了脑缺血再灌注大鼠神经行为学障碍，发挥对抗缺血性脑损伤作用。
Purpose：Stroke, also known as emergent disease, is a neurologicimpairment syndrome, because of cerebral blood circulation disorder. Due to it′s the high level of incidence, death and disability, stroke has emerged asthe second causes of mortality in the human. With the numbers of the elderlyare raised, the incidence of stroke is rise every year, which is regarded asserious threat to human health. Stroke can be classified into two majorcategories: ischemic and hemorrhagic, about3/4of strokes are caused by ischemia.It′s two major way to therapy this disease is: the formation of new blood vesselsand neurprotection (block penumbra neuron death cascade reaction).The new drugs,whose mechanism therapy ischemia were about that,were little effective in clinic.So that how to treat and prevent ischemia is always the challenges faced by themedical..
Ischemic is belong to “ZhongFeng” in traditional chanise medical,and itssymptoms are asthenia in the root and sthenia in the branch. Its root is astheniaof liver yin and kidney yin, and its branch is wind, phlegm fire and stagnationwhich block channels and collaterals of brain. During period of acutely ZhongFeng there are excess of pathogenic factors and deficiency of healthy qi. Sothat principle of treatment to acute Zhong Feng is strengthening heathy qi andeliminate pathogenic factors. Eye acupuncture is belong to acupuncture. But themechanism of eye acupuncture therapy ischemia is obscure, that limit this therapywere used furthermore. There are induced inflammatory reaction excess afterbrain hypoxia, that can damage neuron. In addition that might inducedcompensatory angiogenesis, that can protect neuron. This two therapy-reduceinflammatory and improve angiogenesis, assemebly as. Wethere is the mechanismof eye acupuncture therapy ischemia related that? We reveal the protectedmechanism of action of eye acupuncture therapy to acute ischemia through reducinginflammatory and improving angiogenesis, that proved eye acupuncture therapy ischemia is targets and ways, and provide theory base to clinic therapy.
Material and method：To80SD rats were randomly divided into blank group,sham operation group model group eye acupuncture group. Its were divided intothree sub-group according to2hour′ischemia following by reperfusion by3h24h72h respectively, excluding black group, that plus a total of ten group,every group have eight. The black group was not treated and supplied normal waterand food. the rat model of cerebral ischemia-reperfusion injury was establishedby suture method. sham operation group model was established alike the modelgroup, its difference is suture poll into0.5mm.. The1st eye acupuncture therapyafter reperfusion at“Kindy”,Vindy”,”Sangjiao”,”Xiajiao”points. Andthen the eye acupuncture the eye acupuncture therapy in every12h, until ratsdie. Detection of use of behavioral observations of rats in each group scoreof neurological symptoms; immunohistochemical techniques were employed todetect the microvessel density,the protein expression of NF-KBp65,VCAM-1,VEGFand Flt-1; RT-PCR techniques were employed to detect the expression VEGF/Flt-1HIF-1mRNA; ELASA techniques were employed to detect HIF-1αof serum; Wester blottechniques were employed to detect the protein expression of HIF-1α.And furtherto analyse the indicators of spatial and temporal changes in the law and theeffects of eye acupuncture intervention.
Results：
⑴Model group rat′neurological deficit score is raising to24h afterreperfusion, which is begin to decreased at72h after reperfusion. Eyeacupuncture group′nerve missing sign of rats are improving from3h to72h, whosescores were significantly different from the model ones at24h72h.Eyeacupuncture could effectively neurological deficit score after ischemic ratbrain
⑵In ischemia2h reperfusion3h,the little protein expression of NF-κBp65andVCAM-1in the blank group and sham operation group model group; the immunestaining of NF-κBp65and VCAM-1enhanced, the cytoplasm showed brown which reached the peak in24h after reperfusion and reduced at72h. The expressionof NF-κBp65and VCAM-1were basically same between eye acupuncture group andmodel group, but the eye acupuncture one was less. After treatment of eyeacupuncture, compared to the same period of the model group, the immune stainingof NF-κBp65and VCAM-1of the eye acupuncture group were significantlydifferention. Eye acupuncture could protect brain through inhibitedinflammatory
⑶There are not expression of CD34in the blank group and sham operation groupmodel group;Model group, the expression of CD34microvascular increase rapidlyat24h after reperfusion, and sustainly to72h reperfusion. The expression ofCD34around necrosis of cerebral cortex was increased significantly. Theexpression of CD34was basically same between eye acupuncture group and modelgroup,but the eye acupuncture one was more. eye acupuncture group compared withthe model group were significantly different from reperfusion at different timepoints.This prove eye acupuncture access angiogenges after ischemic.
⑷There are little of HIF-1αin the blank group and sham operation group modelgroup; In serum the of HIF-1α in rat brain increase rapidly at3h afterreperfusion, and which begin decrease until72h reperfusion. the pick of HIF-1αat24h. The expression of HIF-1α was basically same between eye acupuncturegroup and model group, but eye acupuncture group can promote the expression ofHIF-1α,compared with the model group were significantly different fromreperfusion at different time points. Eye acupuncture could protect brainthrough raised HIF-1α
⑸There are little the protein and gene expression of VEGF and its receptorFlk-1were in the blank group and sham operation group model group the proteinand gene expression of VEGF and its receptor Flk-1were rise raptly3h afterreperfusion, which increase sustainly with time reperfusion largely, thatcontinued to72h. After eye acupuncture therapy,the expression of VEGF and Flk-1could promote, which are higher than the corresponding phase of model group,there were significant differences between the two groups. Eye acupuncture could protect brain through improved VEGF/VEGFR
Conclusion：
Eye acupuncture can improve effectively neurological deficit score afterischemic rat brain early, and further promote its recovery of neurologicalfunction with increase eye acupuncture therapy. By the CD34marker, themicrovessel count of eye acupuncture in ischemic areas was more significantlyincreased than the model, indicating that one of mechanism how eye acupuncturetherapy cerebral ischemia is to promote the formation of new blood vessels afterischemia-reperfusion.
Cerebral ischemia-reperfusion can induce the expression of HIF-1α, VEGFand Flk-1. Compensatory increasing in its expression suggested that theyinvolved cascade of ischemia-reperfusion, and make significant role ofprotection in the healing process of the brain injury. eye acupuncture can activemechanism of endogenous angiogenesis, which related to the increase of theexpression of HIF-1α, VEGF and Flk-1. In early ischemia-reperfusion, eyeacupuncture can active HIF-VEGF pathway to promote angiogenesis, through furtheranalysis the indicators of spatial and temporal changes in the law. In addition,eye acupuncture can reduce inflammation like as: NF-κBp65、VCAM-1, so that whichmight reduce damage of ischemic cell. These effects of eye acupuncture mightcorporately reduce neurobehavioral disorders in rate with ischemia-reperfusion,providing effective protective to ischemia.
引文
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