益气养阴活血法改善糖尿病合并脑缺血大鼠记忆能力及神经再生研究

作者：韩辉
论文级别：博士
学科专业名称：中西医结合临床
中文关键词：益气养阴活血法 ; 糖尿病合并脑缺血 ; 神经再生 ; 海马 ; 空间记忆 ; 脑源性神经生长因子
英文关键词：Supplementing Qi ; Nourishing Yin and Activating blood circulation ; Diabetes-associated cerebral ischemia ; Neural regeneration ; Hippocampus ; Spatial memory ; BDNF
学位年度：2011
导师：田金洲
学科代码：100602
学位授予单位：北京中医药大学
论文提交日期：2011-05-01

摘要

1.目的
     前期研究结果显示,气阴两虚、瘀血阻络是糖尿病合并脑缺血的最常见的基本证候,首先建立气阴两虚、瘀血阻络型糖尿病合并脑缺血大鼠模型,观察高血糖对大鼠空间学习记忆能力的影响,以及对海马DG区神经细胞的增殖、分化、存活及BDNF通路的影响,然后观察益气养阴活血中药体内和体外的干预作用,并运用工具药证实BDNF通路在其中的作用。
     2.方法
     2.1采用持续力竭性游泳、甲状腺素片混悬液灌胃、腹腔注射STZ以及线栓法制作糖尿病合并脑缺血气阴两虚、瘀血阻络证大鼠模型,从大鼠的血糖、神经功能、TTC和HE染色结果、一般状态、舌象以及最终的成功率等方面来探讨糖尿病合并脑缺血(气阴两虚、瘀血阻络)病证结合模型的可行性。
     2.2将30只大鼠分为假手术组、脑缺血组以及糖尿病合并脑缺血组,每组10只,用Brdu掺入法结合免疫组化观察糖尿病对脑缺血后大鼠海马齿状回(DG)神经细胞的新生、分化和存活的情况,免疫组化法观察BDNF表达情况,并用Morris水迷宫实验评估糖尿病对脑缺血大鼠空间学习和记忆能力的影响。
     2.3将大鼠分为假手术组、糖尿病合并脑缺血(气阴两虚、瘀血阻络证)模型对照组、益气养阴活血组、益气养阴活血+K252a(BDNF的Trk受体抑制剂)组、益气活血组,每组10只,选用了具有益气养阴活血作用的人参、川芎、玉竹、黄精组合,运用Brdu掺入法、免疫组化和Morris水迷宫实验来观察益气养阴活血法对糖尿病合并脑缺血大鼠空间学习记忆的作用和神经再生机制。
     2.4神经干细胞培养分为4组：正常对照组、缺血再灌注模型组、缺血再灌注后高糖模型组、缺血再灌注后高糖加益气养阴活血药物血清组。Brdu掺入法观察神经干细胞的增殖,甲基噻唑基四唑比色实验检测细胞活性。
     3.结果
     3.1动物模型研究结果表明,糖尿病合并脑缺血(气阴两虚、瘀血阻络)病证结合模型的最终成功率为63%,大鼠在表征、舌象、神经功能缺损、脑组织形态学以及大鼠最终的存活率等几方面指标的综合评价符合该模型的评价体系。
     3.2糖尿病对脑缺血大鼠空间记忆、海马神经再生及BDNF表达的影响
     本研究结果显示,与假手术组和模型组比较,长期高血糖能加重脑缺血大鼠的Morris水迷宫空间学习记忆能力损伤(P<0.05),但糖尿病对于脑缺血后大鼠神经细胞的增殖没有显著的影响(P>0.05),而对于脑缺血后大鼠新增殖细胞的存活及向神经元分化具有明显的抑制作用(P<0.001)。我们的研究还发现,糖尿病合并脑缺血大鼠海马齿状回BDNF表达较单纯脑缺血明显降低(P<0.001)。由于BDNF与神经再生相关,推测糖尿病可能通过抑制BDNF而影响神经再生。
     3.3益气养阴活血药物在糖尿病合并脑缺血大鼠模型中,通过BDNF调节海马的神经再生,并促进空间学习记忆的恢复
     研究结果显示,糖尿病合并脑缺血可使海马齿状回颗粒下层新生细胞增多,但益气养阴活血药物不能促进糖尿病合并脑缺血大鼠新生细胞的进一步增加(P>0.05,)。与糖尿病合并脑缺血组比较,益气养阴活血药物和益气活血药物均可以明显提高新生细胞的存活率、促进新生细胞向神经元分化(P<0.05),同时增加海马齿状回BDNF的表达(P<0.01),并促进糖尿病合并脑缺血大鼠的空间记忆能力的恢复(P<0.05-0.01),其中益气养阴活血药物效果优于益气活血药物(P<0.05)。侧脑室注射BDNF抑制剂K252a可以抑制益气养阴活血药物促进新生细胞存活和向神经元分化的作用(P<0.001),并抑制糖尿病合并脑缺血大鼠的空间记忆能力的恢复(P<0.001)。
     3.4益气养阴活血药物血清对高糖合并缺血再灌注培养模型中大鼠神经干细胞增殖和活力的影响
     结果显示,与正常组比较,脑缺血再灌注后神经干细胞增值显著增加(P<0.01),细胞活力下降(P<0.01)；高糖可抑制神经干细胞的增殖(P<0.05-0.01),降低细胞活力(P<0.05-0.01)；益气养阴活血药物血清可促进神经干细胞的增殖(P<0.01),提高其活力(P<0.01)。我们的体外培养结果证实了益气养阴活血药物能促进脑缺血再灌注合并高糖培养条件下神经干细胞的增殖,提高细胞活力。
     4.结论
     4.1腹腔注射链脲佐菌素、持续力竭性游泳、甲状腺素片混悬液灌胃以及线栓法制作糖尿病合并脑缺血(气阴两虚、瘀血阻络)大鼠模型,从表征、舌象、神经功能缺损、脑组织形态学以及存活率等方面综合评价大鼠病证结合模型是成功的；
     4.2糖尿病可能通过降低BDNF的表达,从而抑制再生神经存活和向神经元分化,进而加重脑缺血后的空间学习记忆障碍；
     4.3益气养阴活血药物可能通过BDNF介导的神经再生和向神经元定向分化而改善空间记忆功能；
     4.4益气养元活血药物可促进脑缺血再灌注后高糖培养大鼠神经干细胞的增殖,提高细胞活力。
1.Objective
     Previous study showed that Qi and Yin Deficiency and blood stasis were the most common Traditional Chinese Medicine (TCM) syndromes of diabetes-associated cerebral ischemia. Here, we establish animal models for the diabetes-associated cerebral ischemia due to Qi and Yin deficiency and blood stasis, and investigate the impact of diabetes on the spatial memory and nerve regeneration in hippocampus and BDNF expression in the cerebral ischemia rats. Furthermore, we evaluate the outcome of TCM of strengthening Qi, maintaining Yin, and promoting blood circulation in treatment of diabetes-associated cerebral ischemia model rats in vivo and in vitro and reveal the role of BDNF in neural regeneration.
     2.Methods
     2.1 We used continuous exhaustive swimming, gavage with thyroxine tablets suspension, and intraperitoneal injection of STZ composite preparations to establish the rat model for the diabetes-associated cerebral ischemia due to Qi and Yin deficiency and blood stasis. We explored the possibilities of the rat model for the diabetes-associated cerebral ischemia due to Qi and Yin deficiency and blood stasis from the aspects of glucose, nervous function, brain morphology, general state, tongue and the overall survival rates.
     2.2 Thirty rats were divided into 3 groups:1) sham,2) cerebral ischemia, and 3) diabetes-associated cerebral ischemia group (n=10 for each group). The BrdU incorporation assay was used to investigate the impact of diabetes on the proliferation, differentiation, and survival of neuron in the rat DG in response to cerebral ischemia. We also employed the immunohistochemistry to analyze the expression of BDNF and used the Morris water maze test to evaluate the effect of diabetes on the spatial learning and memory of cerebral ischemia rats.
     2.3 We set the following experimental groups:1) sham,2) diabetes-associated cerebral ischemia,3) diabetes-associated cerebral ischemia rats treated with TCM of benefiting Qi and maintaining Yin,4) diabetes-associated cerebral ischemia rats treated with TCM of benefiting Qi, maintaining Yin, and promoting blood circulation,5) diabetes-associated cerebral ischemia rats treated with TCM of benefiting Qi and maintaining Yin and K252a (an inhibitor of BDNF Trk receptor), and diabetes-associated cerebral ischemia rats treated with TCM of benefiting Qi and promoting blood circulation (n=10 for each group). We used Ginseng、Ligustrazine、Fragant solomonseal rhizome and Polygonatum Kingianum, which have been shown to benefit Qi, maintain Yin, and promote blood circulation. The BrdU incorporation assay was used to investigate the impact of diabetes on the proliferation, differentiation, and survival of neuron in the rat DG in response to cerebral ischemia. We also employed the immunohistochemistry to analyze the expression of BDNF and used the Morris water maze test to evaluate the effect of diabetes on the spatial learning and memory of cerebral ischemia rats.
     2.4 The cultured neural stem cells were randomly divided into four groups:A) cultured in medium supplementing with normal rat sera, B) cultured in medium supplementing with sera from rats undergoing cerebral ischemia reperfusion, C) cultured in medium supplementing with high concentration glucose and sera from rats undergoing cerebral ischemia reperfusion, and D) cultured in medium supplementing with high concentration glucose and sera from rats undergoing cerebral ischemia reperfusion and treated with TCM for supplementing Qi, nourishing Yin, and promoting blood circulation. The proliferation of neural stem cells was measured using the 5-bro-modeoxyuridine (BrdU) incorporation assay. The activity of neural stem cells was determined using methyl thiazolyl tetrazolium colorimetry.
     3.Results
     3.1 Establishment of animal models
     We used continuous exhaustive swimming, gavage with thyroxine tablets suspension, and intraperitoneal injection of STZ composite preparations to establish the rat model for the diabetes-associated cerebral ischemia due to Qi and Yin deficiency and blood stasis. The results showed that the overall successful rate for establishment of the disease model was 63%. The results showed that the model rats undergoing such treatments displayed phenotypes including tongue symptoms, neurological defects in brain morphology. The overall survival rate was consistent with the comprehensive evaluation index evaluation system for such animal models.
     3.2 The impact of diabetes on the spatial memory and nerve regeneration in hippocampus and BDNF expression in the cerebral infarction rats.
     Our current studies revealed that sustained long-term high blood sugar could increase damage of spatial learning and memory of the cerebral infarction rats in the Morris water maze test (P<0.05). We further investigated the impact of diabetes on neuron regeneration in cerebral infarction rats and found that diabetes significantly inhibited the survival and differentiation of newly proliferating neuron in the cerebral infarction rats(P<0.001), but it had little effect on facilitating neuron proliferation (P>0.05). Moreover, we found that the BDNF expression in the hippocampus of the diabetes-associated cerebral infarction rats was significantly lower than that in the hippocampus of the cerebral infarction without diabetes (P<0.001). Because BDNF expression is critical for neuron regeneration, our data suggested that diabetes might decrease the expression of BDNF, leading to inhibition of neuron differentiation and survival. This in turn affected the spatial learning and memory of cerebral isochemia patients.
     3.3Treatments of the diabetes-associated cerebral ischemia rats with TCM for benefiting Qi, maintaining Yin, and promoting blood circulation promote the recovery of spatial learning and memory via induction of BDNF-mediated nerve regeneration.
     Diabetes-associated cerebral ischemia increased the number of newly proliferating cells in the lower hippocampal dentate gyrus granule, but the treatments with these TCM did not increase the number of newly proliferating cells (P>0.05). It suggested that these TCM did not directly target the cellular proliferation pathway. On the other hand, we observed that the TCM for benefiting Qi, maintaining Yin, and promoting blood circulation or the TCM for benefiting Qi and promoting blood circulation considerably increased the survival rate and promoted the differentiation of newly proliferating neuron (P<0.05). We further found that both TCM significantly increased BDNF expression in the hippocampus of diabetes-associated cerebral ischemia mice(P<0.01) and improved their capability of spatial learning and memory (P<0.05-0.01).In addition, the beneficial effect of the TCM for benefiting Qi, maintaining Yin, and promoting blood circulation was considerably greater than the ones of the TCM for benefiting Qi and promoting blood circulation only (P<0.05) Furthermore, intracerebroventricular injection of the BDNF inhibitor K252a abolished the beneficial effects of the TCM on the survival and differentiation of newly proliferating cells (P<0.001) and on the spatial learning and memory (P<0.001). It suggested that induction of BDNF-mediated neural regeneration and differentiation to neuron plays a key role in the improvement of spatial learning and memory by the TCM for benefiting Qi, maintaining Yin, and promoting blood circulation.
     3.4 Sera containing medicine of supplementing Qi, nourishing Yin and promoting blood circulation increase cell proliferation and viability of neural stem cells of rats with high blood glucose and ischemia/reperfusion injuries.
     We found that sera containing medicine of supplementing Qi, nourishing Yin and promoting blood circulation could significantly increase proliferation (P<0.01) and viability of neural stem cells (P<0.01). MTT results showed that the viability of neural stem cells significantly decreased after reperfusion (P<0.001). Under high glucose tissue culture conditions, the viability of the cell after perfusion further decreased (P<0.05-0.01) compared to the low glucose control group. However, treatments of the neural stem cells with Sera contaning medicine of supplementing Qi, nourishing Yin and promoting blood circulation greatly increased the cellular viability and proliferation (P<0.01). These findings suggested that the joint use of Ginseng, Polygonatum, and Chuanxiong might promote the viability and proliferation of neural stem cells in rats with high blood glucose and ischemia/reperfusion injuries.
     4.Conclusion
     4.1 It is feasible to use continuous exhaustive swimming, gavage with thyroxine tablets suspension, and intraperitoneal injection of STZ composite preparations to establish the rat model for the diabetes-associated cerebral ischemia due to Qi and Yin deficiency and blood stasis
     4.2 Diabetes might inhibit BDNF expression, thus suppressing survival and differentiation of newly regenerated nerve cells in the hippocampus of the cerebral infarction rats and consequently affecting spatial learning and memory of cerebral infarction rats.
     4.3 TCM for benefiting Qi, maintaining Yin, and promoting blood circulation promote the recovery of spatial learning and memory via induction of BDNF-mediated nerve regeneration.
     4.4 Chinese prescription of supplementing Qi, nourishing Yin and promoting blood circulation can promote the proliferation and the activities of neural stem cells cultured in high concentration glucose medium from rats undergoing cerebral ischemia reperfusion.

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