通络化痰胶囊及其有效成分对脑缺血再灌注损伤的神经保护作用及机制研究
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摘要
缺血脑组织在一定条件下恢复血液供应后,出现了更加严重的脑功能障碍和结构损伤,称之为脑缺血-再灌注损伤。常见于休克、DIC微循环再通、脑血管栓塞再通、心肺脑复苏等。缺血性脑血管疾病是神经科常见疾病,其致残、致死率高,治疗原则是及时恢复缺血区的血液供应,但同时也带来了再灌注损伤,抑制再灌注损伤已成为治疗缺血性脑血管疾病的重要环节。随着现代医学对脑缺血-再灌注损伤病理生理机制认识的不断深化,近些年来中医药防治脑缺血-再灌注损伤的研究发展迅速,涉及到中药药理、方剂学、针刺作用机理等多方面内容。许多研究业已证实中医药对脑缺血-再灌注损伤有保护作用
通络化痰胶囊由范吉平教授根据《中风病诊断、疗效评定标准》确定的中风病的病类、证候分类方法,选取中风病最常见的风痰瘀血痹阻脉络证,结合导师王永炎院士“毒损脑络”的学术思想,以及自己治疗中风病临床经验研发而成,由熊胆粉、天麻、三七、丹参、天竺黄、大黄等药物组成,具有活血通络、化痰熄风的功效,主治中风病中经络、痰瘀阻络证,症见半身不遂,口眼歪斜,舌强语謇,或不语,偏身麻木,口角流涎,唇甲色暗,舌苔厚腻,舌质暗,或有瘀点,瘀斑,舌底脉络瘀暗,脉涩或弦滑。
通络化痰前期药效学实验研究表明通络化痰胶囊能明显改善脑缺血所致的大鼠的偏瘫体征及神经系统症状,缩小脑梗塞灶面积,能明显降低脑缺血时脑血管的通透性、降低脑组织的含水量,减轻脑水肿和神经元的继发性损害,明显减轻大鼠局灶性脑缺血的病理形态学改变,降低大鼠局灶性脑缺血时血小板聚集率,能明显延缓大鼠血栓的形成时间,抑制血栓形成,另外还能增强小鼠抗缺氧的能力。
本实验试图研究通络化痰胶囊及其有效成分熊胆的神经保护作用及机制,为通络化痰胶囊防治脑缺血-再灌注损伤的治疗作用提供客观的实验依据。
研究目的：
1.探讨通络化痰胶囊的神经保护作用及机制,为通络化痰胶囊防治脑缺血-再灌注损伤的治疗作用提供客观的实验依据。
2.探讨通络化痰胶囊有效成分熊胆粉的神经保护作用及机制。
研究方法：
采用具有线栓法模拟局灶性脑缺血-再灌注损伤大鼠模型,根据神经功能评分和行为学测试方法检测实验动物的神经功能恢复程度、利用HE染色和尼氏染色的方法检测脑组织的病理学改变、采用免疫组化方法检测脑组织中GFAP、 NF-kB、TNF-a、ICAM-1、IL-1β、IL-8的表达,采用westernblot技术检测脑组织中GFAP、NF-kB的蛋白表达；采用RT-PCR方法检测脑组织中GFAP、NF-kB的基因表达。
研究结果：
1.圆柱实验神经行为学结果
假手术组手术后第1天不对称分值较空白组增高(P<0.05),之后恢复至正常水平(与空白对照组比较P>0.05)。模型组手术后第1天不对称分值较空白对照组明显增高(P<0.05),第7天时未恢复至正常水平(P<0.05)。阳性药组手术后第1天不对称分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天不对称分值与模型组相比降低(P<0.05)。低剂量组手术后第1天不对称分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天不对称分值与模型组相比无统计学差异(P>0.05)。中剂量组手术后第1天不对称分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天不对称分值与模型组、低剂量组相比降低(P<0.05),与阳性药组比较无统计学差异(P>0.05)。高剂量组手术后第1天不对称分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天不对称分值与模型组、低剂量组相比降低(P<0.05),与阳性药组、中剂量组比较无统计学差异(P>0.05)。熊胆粉组手术后第1天不对称分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天不对称分值与模型组、低剂量组相比降低(P<0.05),与阳性药组、中剂量组、高剂量组比较无统计学差异(P>0.05)。
2.窄通道-夹角神经行为学结果
假手术组：手术后第1天转身分值较空白对照组增高(P<0.05)。第7天时未恢复至正常水平(P<0.05)。模型组：手术后第1天转身分值较空白对照组明显增高(P<0.05),第7天时未恢复至正常水平(P<0.05)。阳性药组：手术后第1天转身分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天转身分值与模型组相比降低(P<0.05)。低剂量组：手术后第1天转身分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天转身分值与模型组相比无统计学差异(P>0.05)。中剂量组：手术后第1天转身分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天转身分值与模型组、低剂量组相比降低(P<0.05),与阳性药组比较无统计学差异(P>0.05)。高剂量组：手术后第1天转身分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天转身分值与模型组、低剂量组相比降低(P<0.05),与阳性药组、中剂量组比较无统计学差异(P>0.05)。熊胆粉组：手术后第1天转身分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天转身分值与模型组、低剂量组相比降低(P<0.05),与阳性药组、中剂量组、高剂量组比较无统计学差异(P>0.05)。
3.大鼠脑组织病理形态学改变
肉眼观察空白组、假手术组、阳性药组及给药高剂量组、中剂量组、低剂量组和模型组共八组大鼠脑组织未见明显病变。
镜下HE染色观察示空白组大鼠脑组织大脑、小脑各级神经细胞未见有病理形态学改变,小脑浦肯野细胞未见有退行性改变,结构正常。假手术组大鼠脑组织大脑、小脑各级神经细胞未见变形,小血管有轻度充血,未见明显病变。模型组大鼠脑组织大脑、小脑神经细胞有缺血性改变,细胞尼氏小体消失、胞核固缩、核仁消失,部分细胞染色灰色,有退行性变；有的细胞膜与周围分界清楚,染色布均匀。小脑的浦肯野细胞及海马区细胞未见明显改变。给药三个剂量组、阳性药组和熊胆粉组所送检大鼠脑组织：与模型组相比,大脑神经细胞的病变有不同程度改变。
尼氏染色镜下观察示空白对照组大鼠脑细胞内尼氏小体显示多见。假手术组大鼠脑细胞内尼氏小体显示多见。模型组大鼠脑细胞内尼氏小体明显减少。给药三个剂量组、阳性药组和熊胆粉组所送检大鼠脑组织细胞各组尼氏小体与模型组相比有不同程度增加
4.大鼠缺血再灌注7天后免疫组化法测定大鼠脑组织中GFAP.NF-Kb、TNF-a、ICAM-1、IL-1β、IL-8含量结果显示：通络化痰高、中、低剂量组、熊胆组、阳性药组海马CA1区GFAP表达均显著低于模型组(P<0.05),阳性药组皮质区GFAP表达低于模型组(P<0.05),通络化痰高、中、低剂量组、熊胆组与模型组相比,无显著性差异(P>0.05)
阳性药组、低剂量组海马区和皮层区NF-Kb表达低于模型组(P<0.05)。通络化痰高、中剂量组、熊胆组NF-Kb表达均显著低于阳性药组(P<0.05)；模型组脑组织皮层区及海马区TNF-α、ICAM-1、 IL-1β、IL-8水平高于空白对照组及假手术组(P<0.05),与模型组相比,通络化痰各组、阳性药组、熊胆组ICAM-1水平降低(P<0.05),通络化痰高剂量组、熊胆组ICAM-1降低水平高于阳性药组、低剂量组(P<0.05)。
5.大鼠缺血再灌注7天后Western-b1ot法测定大鼠脑组织中GFAP、NF-Kb蛋白含量结果显示：通络化痰各组、熊胆组、阳性药组GFAP蛋白表达均低于模型组(P<0.05),用药各组间GFAP蛋白表达无差异(P>0.05)。通络化痰各组、熊胆组、阳性药组NF-K蛋白表达均低于模型组(P<0.05)。通络化痰高、中剂量组、熊胆组NF-Kb蛋白表达均显著低于通络化痰低剂量组(P<0.05)。
6.大鼠缺血再灌注7天后测定大鼠脑组织中GFAP、NF-KbmRNA含量测定结果显示：通络化痰各组、熊胆组、阳性药组NF-KbmRNA表达均低于模型组(P<0.05),用药各组之间NF-Kb表达无差异(P>0.05)；通络化痰各组、熊胆组、阳性药组GFAP mRNA表达均低于模型组(P<0.05)。用药各组之间GFAP mRNA表达无差异(P>0.05)。
结论：
通络化痰胶囊及其有效成分熊胆粉对神经系统具有保护作用,可减轻脑缺血-再灌注损伤大鼠的脑组织损伤,其作用的发挥可能与其可以降低缺血再灌注损伤后脑组织TNF-α、NF-Kb、ICAM-1、IL-1β、IL-8、GFAP等相关因子的表达相关。
After Ischemic brain tissue restoring blood supply in certain conditions, there was a more serious brain dysfunction and structural damage, known as cerebral ischemia-repe-rfusion injury, which is Common in shock, DIC reperfusion of microcirculation and Cerebrovascular embolization through again, cardiopulmonary cerebral resuscitation etc. Ischemic cerebral vascular disease is a neurological disease, which has a high rates of disability and death. The treatment principle is to restore a blood supply, but which also brought a reperfusion injury. Inhibiting reperfusion injury have become a important part of treatment of ischemic cerebral vascular diseases. With modern medicine on cerebral ischemia-reperfusion injury in deepening understanding of pathophysiological mechanisms, in recent years, Chinese medicine in preventing and treating cerebral ischemia-reperfusion injury of rapid development, related to Pharmacology, pharmacology, mechanism of acupuncture, and other content. Many studies have confirmed that Chinese medicine has a protective effect on cerebral ischemia-reperfusion injury.
TongLuoHuaTan capsule was invented by Professor Fan Jiping according to the Antihypertensive and Syndrome classification method of stroke disease determined by the book "Diagnosis and clinical efficacy evaluation standards of stroke", and selecting the most common stroke type of wind phlegm blood stasis bi resistance thread card, combinating mentor Wang yongyan fellow's academic thought "heat-toxic affecting the brain collaterals", and with himself s clinical treatment experience of stroke disease. The capsule is made by gall powder, Gastrodia elata, Sanqi, Salvia miltiorrhiza, Tianzhu yellow, and rhubarb, which has a effect of promoting blood circulation, removing obstruction in channels, peliminating phlegm, calming wind. Its major effects are treating stroke precursor caused by phlegm-stasis in channels, syndrome of intermingled phlegm and blood stasis,which show symptoms of hemiplegia, facial paralysis, stiff tongue and impeded speech, or aphasia, hemianesthesia, slobbering, lip color a dark, tongue thick and greasy, tongue qualitative dark, petechia or bruise, tongue base vein stasis and dark, pulse astringent or wiry slide.
Early effect experimental research of TongLuoHuaTan capsule indicates that TongLuoHuaTan capsule can clearly improve hemiplegia signs and the nervous system symptoms of large rat due to brain deficiency blood, narrow brain infarction focal area, clearly reduce the permeability of blood vessel of brain when it is cerebral ischemia, and reduce the moisture of brain organization, reduce brain edema and secondary lesion of neurons, significantly reduce large rat Council focal sexual brain deficiency blood of pathology morphology change, reduced pathomorphology change in focal cerebral ischemia of rat, clearly reduce platelet aggregation rate in focal cerebral ischemia of rat, significantly delay rats blood clots forming time, suppression thrombosis formed, Also can enhance the ability of hypoxia in mice.
This experiment tried to study the neuroprotective effects and mechanism of TongLuoHuaTan capsule and its effective components of bear gall, provide objective experiment basis of TongLuoHuaTan capsule in preventing and treating cerebral ischemia-reperfusion injury.
Research objectives:
1. Discuss on neuroprotective effect of TongLuoHuaTan capsule and provide objective experiment basis of TongLuoHuaTan capsule in preventing and treating cerebral ischemia-reperfusion injury.
2. Discussion on neuro-protective effect and mechanism of the effective components of bear gall of TongLuoHuaTan capsule.
Research methods:
Using Suture-occluded method to simulation focal cerebral ischemia-reperfusion injury rat model, test experimental animals'neurological recovery degree According to the nerve functional score and behavioral testing methods, test brain's pathology change by using HE dyeing and Nepal's dyeing method, and using immunohistochemical staining to detect the expression of GFAP, NF-kB, TNF-a, ICAM-1, IL-1beta, IL-8in brain organization, using westernblot technology to detect the protein expression of GFAP, and NF-kB in the brain organization, using RT-PCR method to detect the gene expression of GFAP and NF-kB in the brain tissue.
Research results:
1. Nerve behavior results of Cylinder Test
1day after surgery, asymmetric score of sham-operation group is increased compared with the blank Group (P<0.05), and then back to normal level (compared with the blank control group P>0.05).1day after surgery, asymmetric score of the model group is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05).1day after surgery, asymmetric score of the positive drug group is significantly increased compared with the blank control group (P<0.05), which did not return to normallevels on the7th day (P<0.05), asymmetrical score of the7th day is reduced compared to the model group (P<0.05).1day after surgery, asymmetric score of the low dose group is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05), asymmetrical score of the7th day was no statistical difference compared to the model group (P>0.05).1day after surgery, asymmetric score of the medial-dose group is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05), asymmetrical score of the7th day is lower compared to the model group and low dose group (P<0.05), which has no statistically significant difference compared with positive Group (P>0.05).1day after surgery, asymmetric score of the high-dose group is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05), asymmetrical score of the7th day is lower compared to the model group and low dose group (P<0.05), which has no statistically significant difference compared with positive Group, middle-doze group(P>0.05).1day after surgery, asymmetric score of the bear bile powder group is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05), asymmetrical score of the7th day is lower compared to the model group and low dose group (P<0.05), which has no statistically significant difference compared with positive Group, middle-doze group and high doze group (P>0.05).
2. Nerve behavior results of Narrow-alley Corner Test
Sham-operation group:1day after surgery, turning score is increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05). Model group:1day after surgery, turning score is significantly increased compared with the blank control group (P<0.05), which did not return to normallevels on the7th day (P<0.05). Positive groups:1day after surgery, turning score is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05). Turning score of the7th day is lower compared to the model group (P<0.05). Low dose group:1day after surgery, turning score is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05), Turning score of the7th day is no statistical difference compared to the model group (P>0.05).Middle-dose group:1day after surgery, turning score is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05), Turning score of the7th day is reduced compared to the model group and low-doze group (P>0.05). High dose group:1day after surgery, turning score is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05), Turning score of the7th day is reduced compared to the model group and low-doze group (P<0.05), which has no statistically significant difference compared with positive Group, middle-doze group (P>0.05). Group of bear bile powder:1day after surgery, turning score is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05), Turning score of the7th day is reduced compared to the model group and low-doze group (P<0.05), which has no statistically significant difference compared with positive Group, middle-doze group and high doze group (P>0.05).
3. Pathological morphological changes in brain tissues of rats
Macroscopic observation shows that blank group, Sham-operation group, positive drug group and the high-dose group, middle-dose groups and low dose groups and model group for a total of eight group no significant pathological changes of rat brain.
Microscopically HE dyeing shows the blank set of brain tissue in rats, cerebellar neuronal has no pathological changes at all levels, no degeneration in cerebellar Purkinje cells, and structural is normal. Sham-operation set of brain tissue of rat has no deformation on cerebellar neurons at all levels in the brain,, small vessels have mild congestion, no significant disease. Model set of brain tissue in rats has ischemic change on cerebrum and cerebellum, cell's nissl bodies disappears, cell nuclear pyknosis, nucleoli disappear, some staining to be gray, degeneration; some boundaries around the cell membrane are clear, stained uniform. Purkinje cells of the cerebellum and hippocampal cells do not see obvious changes. Three dose groups, drug-positive Group and by the Group of bear bile powder in rat brain: compared with the model group, all have different degree change of nerve cells of the brain.
Nissl staining microscopic observation shows in the blank control group Nissl's body shows more in brain cell of rat. Sham-operation group shows more Nissl's body in the brain cells of rats. Model groups of brain cells of rats have a marked decline in Nepal's small body. Three dose groups, drug-positive Group and bear bile powder group, compared to the model Group's smaller body, have increased in different levels.
4.7days after Rats'ischemia-reperfusion, using immunohistochemistry to determine deficiency blood then perfusion using Immunohistochemical method to detect the expression of GFAP, and NF-k b, and TNF-a, and ICAM-1, and IL-1β in thel brain tissue of rats, the results display that the expression of GFAP in Hippocampus CA1area of high doze group, middle doze group, low-doze group, bear gall group are significantly lower than that of model group (P<0.05), the expression of GFAP in cortex area of positive drug group is lower than than of model group (P<0.05), that of high doze group, middle doze group, low-doze group, bear gall group and positive drug group have no significant differences compared to model group (P>0.05); The expression of NF-Kb of drug-positive Group, and the low-dose group are lower than that of the model group (P<0.05). The expression of TNF-a, ICAM-1, IL-1β and IL-8in hippocampus and cortex area of brain tissue of model group are higher than than of the blank controller group and sham-operation group (P<0.05); The expression of NF-Kb of high doze group, middle doze group and bear gall group are all significantly lower than that of positive drug group (P<0.05), compared with the model group, the expression of ICAM-1of doze groups, positive drug group and bear gall group are lower (P<0.05), the reduce level of the expression of ICAM-1of the high doze group and bear gall group are higher than that of positive drug group and low doze group (P<0.05).
5.7days after Rats'ischemia-reperfusion, using westernblot technology to detect the protein expression of GFAP and NF-kB in the brain organization, results shows:the protein expression of GFAP of doze groups, bear gall group and positive drug group are all lower than that of model group (P<0.05), and the protein expression of GFAP of doze groups have no difference (P>0.05). The protein expression of NF-kb in doze groups, bear bile group, positive drug group are less than that of the model group (P<0.05). The protein expression of NF-Kb in high doze group, middle doze group and bear bile group are significantly less than that of the low dose group (P<0.05).
6.7days after Rats、ischemia-reperfusion, to detect the mRNA expression of GFAP and NF-kB in the brain organization, results shows:the mRNA expression of NF-kB of doze groups, bear gall group and positive drug group are all lower than that of model group (P<0.05), the mRNA expression of NF-kB of doze groups have no difference (P>0.05); the mRNA expression of GFAP of doze groups, bear gall group and positive drug group are all lower than that of model group (P<0.05), the mRNA expression of GFAP of doze groups have no difference (P>0.05).
Conclusions:
TongLuoHuaTan capsule and its active ingredients bear bile powder have a Significant neural protection, can reduce cerebral ischemia-reperfusion injury in rats with Brain tissue damage, which may due to its reduce the expression of TNF-alpha, NF-k b, ICAM-1, IL-1, R, IL-8, of GFAP and other related factors after ischemia-reperfusion injury in cerebral organization.
通络化痰胶囊由范吉平教授根据《中风病诊断、疗效评定标准》确定的中风病的病类、证候分类方法,选取中风病最常见的风痰瘀血痹阻脉络证,结合导师王永炎院士“毒损脑络”的学术思想,以及自己治疗中风病临床经验研发而成,由熊胆粉、天麻、三七、丹参、天竺黄、大黄等药物组成,具有活血通络、化痰熄风的功效,主治中风病中经络、痰瘀阻络证,症见半身不遂,口眼歪斜,舌强语謇,或不语,偏身麻木,口角流涎,唇甲色暗,舌苔厚腻,舌质暗,或有瘀点,瘀斑,舌底脉络瘀暗,脉涩或弦滑。
通络化痰前期药效学实验研究表明通络化痰胶囊能明显改善脑缺血所致的大鼠的偏瘫体征及神经系统症状,缩小脑梗塞灶面积,能明显降低脑缺血时脑血管的通透性、降低脑组织的含水量,减轻脑水肿和神经元的继发性损害,明显减轻大鼠局灶性脑缺血的病理形态学改变,降低大鼠局灶性脑缺血时血小板聚集率,能明显延缓大鼠血栓的形成时间,抑制血栓形成,另外还能增强小鼠抗缺氧的能力。
本实验试图研究通络化痰胶囊及其有效成分熊胆的神经保护作用及机制,为通络化痰胶囊防治脑缺血-再灌注损伤的治疗作用提供客观的实验依据。
研究目的：
1.探讨通络化痰胶囊的神经保护作用及机制,为通络化痰胶囊防治脑缺血-再灌注损伤的治疗作用提供客观的实验依据。
2.探讨通络化痰胶囊有效成分熊胆粉的神经保护作用及机制。
研究方法：
采用具有线栓法模拟局灶性脑缺血-再灌注损伤大鼠模型,根据神经功能评分和行为学测试方法检测实验动物的神经功能恢复程度、利用HE染色和尼氏染色的方法检测脑组织的病理学改变、采用免疫组化方法检测脑组织中GFAP、 NF-kB、TNF-a、ICAM-1、IL-1β、IL-8的表达,采用westernblot技术检测脑组织中GFAP、NF-kB的蛋白表达；采用RT-PCR方法检测脑组织中GFAP、NF-kB的基因表达。
研究结果：
1.圆柱实验神经行为学结果
假手术组手术后第1天不对称分值较空白组增高(P<0.05),之后恢复至正常水平(与空白对照组比较P>0.05)。模型组手术后第1天不对称分值较空白对照组明显增高(P<0.05),第7天时未恢复至正常水平(P<0.05)。阳性药组手术后第1天不对称分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天不对称分值与模型组相比降低(P<0.05)。低剂量组手术后第1天不对称分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天不对称分值与模型组相比无统计学差异(P>0.05)。中剂量组手术后第1天不对称分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天不对称分值与模型组、低剂量组相比降低(P<0.05),与阳性药组比较无统计学差异(P>0.05)。高剂量组手术后第1天不对称分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天不对称分值与模型组、低剂量组相比降低(P<0.05),与阳性药组、中剂量组比较无统计学差异(P>0.05)。熊胆粉组手术后第1天不对称分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天不对称分值与模型组、低剂量组相比降低(P<0.05),与阳性药组、中剂量组、高剂量组比较无统计学差异(P>0.05)。
2.窄通道-夹角神经行为学结果
假手术组：手术后第1天转身分值较空白对照组增高(P<0.05)。第7天时未恢复至正常水平(P<0.05)。模型组：手术后第1天转身分值较空白对照组明显增高(P<0.05),第7天时未恢复至正常水平(P<0.05)。阳性药组：手术后第1天转身分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天转身分值与模型组相比降低(P<0.05)。低剂量组：手术后第1天转身分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天转身分值与模型组相比无统计学差异(P>0.05)。中剂量组：手术后第1天转身分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天转身分值与模型组、低剂量组相比降低(P<0.05),与阳性药组比较无统计学差异(P>0.05)。高剂量组：手术后第1天转身分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天转身分值与模型组、低剂量组相比降低(P<0.05),与阳性药组、中剂量组比较无统计学差异(P>0.05)。熊胆粉组：手术后第1天转身分值较空白对照组明显增高(P<0.05),第7天未恢复至正常水平(P<0.05),第7天转身分值与模型组、低剂量组相比降低(P<0.05),与阳性药组、中剂量组、高剂量组比较无统计学差异(P>0.05)。
3.大鼠脑组织病理形态学改变
肉眼观察空白组、假手术组、阳性药组及给药高剂量组、中剂量组、低剂量组和模型组共八组大鼠脑组织未见明显病变。
镜下HE染色观察示空白组大鼠脑组织大脑、小脑各级神经细胞未见有病理形态学改变,小脑浦肯野细胞未见有退行性改变,结构正常。假手术组大鼠脑组织大脑、小脑各级神经细胞未见变形,小血管有轻度充血,未见明显病变。模型组大鼠脑组织大脑、小脑神经细胞有缺血性改变,细胞尼氏小体消失、胞核固缩、核仁消失,部分细胞染色灰色,有退行性变；有的细胞膜与周围分界清楚,染色布均匀。小脑的浦肯野细胞及海马区细胞未见明显改变。给药三个剂量组、阳性药组和熊胆粉组所送检大鼠脑组织：与模型组相比,大脑神经细胞的病变有不同程度改变。
尼氏染色镜下观察示空白对照组大鼠脑细胞内尼氏小体显示多见。假手术组大鼠脑细胞内尼氏小体显示多见。模型组大鼠脑细胞内尼氏小体明显减少。给药三个剂量组、阳性药组和熊胆粉组所送检大鼠脑组织细胞各组尼氏小体与模型组相比有不同程度增加
4.大鼠缺血再灌注7天后免疫组化法测定大鼠脑组织中GFAP.NF-Kb、TNF-a、ICAM-1、IL-1β、IL-8含量结果显示：通络化痰高、中、低剂量组、熊胆组、阳性药组海马CA1区GFAP表达均显著低于模型组(P<0.05),阳性药组皮质区GFAP表达低于模型组(P<0.05),通络化痰高、中、低剂量组、熊胆组与模型组相比,无显著性差异(P>0.05)
阳性药组、低剂量组海马区和皮层区NF-Kb表达低于模型组(P<0.05)。通络化痰高、中剂量组、熊胆组NF-Kb表达均显著低于阳性药组(P<0.05)；模型组脑组织皮层区及海马区TNF-α、ICAM-1、 IL-1β、IL-8水平高于空白对照组及假手术组(P<0.05),与模型组相比,通络化痰各组、阳性药组、熊胆组ICAM-1水平降低(P<0.05),通络化痰高剂量组、熊胆组ICAM-1降低水平高于阳性药组、低剂量组(P<0.05)。
5.大鼠缺血再灌注7天后Western-b1ot法测定大鼠脑组织中GFAP、NF-Kb蛋白含量结果显示：通络化痰各组、熊胆组、阳性药组GFAP蛋白表达均低于模型组(P<0.05),用药各组间GFAP蛋白表达无差异(P>0.05)。通络化痰各组、熊胆组、阳性药组NF-K蛋白表达均低于模型组(P<0.05)。通络化痰高、中剂量组、熊胆组NF-Kb蛋白表达均显著低于通络化痰低剂量组(P<0.05)。
6.大鼠缺血再灌注7天后测定大鼠脑组织中GFAP、NF-KbmRNA含量测定结果显示：通络化痰各组、熊胆组、阳性药组NF-KbmRNA表达均低于模型组(P<0.05),用药各组之间NF-Kb表达无差异(P>0.05)；通络化痰各组、熊胆组、阳性药组GFAP mRNA表达均低于模型组(P<0.05)。用药各组之间GFAP mRNA表达无差异(P>0.05)。
结论：
通络化痰胶囊及其有效成分熊胆粉对神经系统具有保护作用,可减轻脑缺血-再灌注损伤大鼠的脑组织损伤,其作用的发挥可能与其可以降低缺血再灌注损伤后脑组织TNF-α、NF-Kb、ICAM-1、IL-1β、IL-8、GFAP等相关因子的表达相关。
After Ischemic brain tissue restoring blood supply in certain conditions, there was a more serious brain dysfunction and structural damage, known as cerebral ischemia-repe-rfusion injury, which is Common in shock, DIC reperfusion of microcirculation and Cerebrovascular embolization through again, cardiopulmonary cerebral resuscitation etc. Ischemic cerebral vascular disease is a neurological disease, which has a high rates of disability and death. The treatment principle is to restore a blood supply, but which also brought a reperfusion injury. Inhibiting reperfusion injury have become a important part of treatment of ischemic cerebral vascular diseases. With modern medicine on cerebral ischemia-reperfusion injury in deepening understanding of pathophysiological mechanisms, in recent years, Chinese medicine in preventing and treating cerebral ischemia-reperfusion injury of rapid development, related to Pharmacology, pharmacology, mechanism of acupuncture, and other content. Many studies have confirmed that Chinese medicine has a protective effect on cerebral ischemia-reperfusion injury.
TongLuoHuaTan capsule was invented by Professor Fan Jiping according to the Antihypertensive and Syndrome classification method of stroke disease determined by the book "Diagnosis and clinical efficacy evaluation standards of stroke", and selecting the most common stroke type of wind phlegm blood stasis bi resistance thread card, combinating mentor Wang yongyan fellow's academic thought "heat-toxic affecting the brain collaterals", and with himself s clinical treatment experience of stroke disease. The capsule is made by gall powder, Gastrodia elata, Sanqi, Salvia miltiorrhiza, Tianzhu yellow, and rhubarb, which has a effect of promoting blood circulation, removing obstruction in channels, peliminating phlegm, calming wind. Its major effects are treating stroke precursor caused by phlegm-stasis in channels, syndrome of intermingled phlegm and blood stasis,which show symptoms of hemiplegia, facial paralysis, stiff tongue and impeded speech, or aphasia, hemianesthesia, slobbering, lip color a dark, tongue thick and greasy, tongue qualitative dark, petechia or bruise, tongue base vein stasis and dark, pulse astringent or wiry slide.
Early effect experimental research of TongLuoHuaTan capsule indicates that TongLuoHuaTan capsule can clearly improve hemiplegia signs and the nervous system symptoms of large rat due to brain deficiency blood, narrow brain infarction focal area, clearly reduce the permeability of blood vessel of brain when it is cerebral ischemia, and reduce the moisture of brain organization, reduce brain edema and secondary lesion of neurons, significantly reduce large rat Council focal sexual brain deficiency blood of pathology morphology change, reduced pathomorphology change in focal cerebral ischemia of rat, clearly reduce platelet aggregation rate in focal cerebral ischemia of rat, significantly delay rats blood clots forming time, suppression thrombosis formed, Also can enhance the ability of hypoxia in mice.
This experiment tried to study the neuroprotective effects and mechanism of TongLuoHuaTan capsule and its effective components of bear gall, provide objective experiment basis of TongLuoHuaTan capsule in preventing and treating cerebral ischemia-reperfusion injury.
Research objectives:
1. Discuss on neuroprotective effect of TongLuoHuaTan capsule and provide objective experiment basis of TongLuoHuaTan capsule in preventing and treating cerebral ischemia-reperfusion injury.
2. Discussion on neuro-protective effect and mechanism of the effective components of bear gall of TongLuoHuaTan capsule.
Research methods:
Using Suture-occluded method to simulation focal cerebral ischemia-reperfusion injury rat model, test experimental animals'neurological recovery degree According to the nerve functional score and behavioral testing methods, test brain's pathology change by using HE dyeing and Nepal's dyeing method, and using immunohistochemical staining to detect the expression of GFAP, NF-kB, TNF-a, ICAM-1, IL-1beta, IL-8in brain organization, using westernblot technology to detect the protein expression of GFAP, and NF-kB in the brain organization, using RT-PCR method to detect the gene expression of GFAP and NF-kB in the brain tissue.
Research results:
1. Nerve behavior results of Cylinder Test
1day after surgery, asymmetric score of sham-operation group is increased compared with the blank Group (P<0.05), and then back to normal level (compared with the blank control group P>0.05).1day after surgery, asymmetric score of the model group is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05).1day after surgery, asymmetric score of the positive drug group is significantly increased compared with the blank control group (P<0.05), which did not return to normallevels on the7th day (P<0.05), asymmetrical score of the7th day is reduced compared to the model group (P<0.05).1day after surgery, asymmetric score of the low dose group is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05), asymmetrical score of the7th day was no statistical difference compared to the model group (P>0.05).1day after surgery, asymmetric score of the medial-dose group is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05), asymmetrical score of the7th day is lower compared to the model group and low dose group (P<0.05), which has no statistically significant difference compared with positive Group (P>0.05).1day after surgery, asymmetric score of the high-dose group is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05), asymmetrical score of the7th day is lower compared to the model group and low dose group (P<0.05), which has no statistically significant difference compared with positive Group, middle-doze group(P>0.05).1day after surgery, asymmetric score of the bear bile powder group is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05), asymmetrical score of the7th day is lower compared to the model group and low dose group (P<0.05), which has no statistically significant difference compared with positive Group, middle-doze group and high doze group (P>0.05).
2. Nerve behavior results of Narrow-alley Corner Test
Sham-operation group:1day after surgery, turning score is increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05). Model group:1day after surgery, turning score is significantly increased compared with the blank control group (P<0.05), which did not return to normallevels on the7th day (P<0.05). Positive groups:1day after surgery, turning score is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05). Turning score of the7th day is lower compared to the model group (P<0.05). Low dose group:1day after surgery, turning score is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05), Turning score of the7th day is no statistical difference compared to the model group (P>0.05).Middle-dose group:1day after surgery, turning score is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05), Turning score of the7th day is reduced compared to the model group and low-doze group (P>0.05). High dose group:1day after surgery, turning score is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05), Turning score of the7th day is reduced compared to the model group and low-doze group (P<0.05), which has no statistically significant difference compared with positive Group, middle-doze group (P>0.05). Group of bear bile powder:1day after surgery, turning score is significantly increased compared with the blank control group (P<0.05), which did not return to normal levels on the7th day (P<0.05), Turning score of the7th day is reduced compared to the model group and low-doze group (P<0.05), which has no statistically significant difference compared with positive Group, middle-doze group and high doze group (P>0.05).
3. Pathological morphological changes in brain tissues of rats
Macroscopic observation shows that blank group, Sham-operation group, positive drug group and the high-dose group, middle-dose groups and low dose groups and model group for a total of eight group no significant pathological changes of rat brain.
Microscopically HE dyeing shows the blank set of brain tissue in rats, cerebellar neuronal has no pathological changes at all levels, no degeneration in cerebellar Purkinje cells, and structural is normal. Sham-operation set of brain tissue of rat has no deformation on cerebellar neurons at all levels in the brain,, small vessels have mild congestion, no significant disease. Model set of brain tissue in rats has ischemic change on cerebrum and cerebellum, cell's nissl bodies disappears, cell nuclear pyknosis, nucleoli disappear, some staining to be gray, degeneration; some boundaries around the cell membrane are clear, stained uniform. Purkinje cells of the cerebellum and hippocampal cells do not see obvious changes. Three dose groups, drug-positive Group and by the Group of bear bile powder in rat brain: compared with the model group, all have different degree change of nerve cells of the brain.
Nissl staining microscopic observation shows in the blank control group Nissl's body shows more in brain cell of rat. Sham-operation group shows more Nissl's body in the brain cells of rats. Model groups of brain cells of rats have a marked decline in Nepal's small body. Three dose groups, drug-positive Group and bear bile powder group, compared to the model Group's smaller body, have increased in different levels.
4.7days after Rats'ischemia-reperfusion, using immunohistochemistry to determine deficiency blood then perfusion using Immunohistochemical method to detect the expression of GFAP, and NF-k b, and TNF-a, and ICAM-1, and IL-1β in thel brain tissue of rats, the results display that the expression of GFAP in Hippocampus CA1area of high doze group, middle doze group, low-doze group, bear gall group are significantly lower than that of model group (P<0.05), the expression of GFAP in cortex area of positive drug group is lower than than of model group (P<0.05), that of high doze group, middle doze group, low-doze group, bear gall group and positive drug group have no significant differences compared to model group (P>0.05); The expression of NF-Kb of drug-positive Group, and the low-dose group are lower than that of the model group (P<0.05). The expression of TNF-a, ICAM-1, IL-1β and IL-8in hippocampus and cortex area of brain tissue of model group are higher than than of the blank controller group and sham-operation group (P<0.05); The expression of NF-Kb of high doze group, middle doze group and bear gall group are all significantly lower than that of positive drug group (P<0.05), compared with the model group, the expression of ICAM-1of doze groups, positive drug group and bear gall group are lower (P<0.05), the reduce level of the expression of ICAM-1of the high doze group and bear gall group are higher than that of positive drug group and low doze group (P<0.05).
5.7days after Rats'ischemia-reperfusion, using westernblot technology to detect the protein expression of GFAP and NF-kB in the brain organization, results shows:the protein expression of GFAP of doze groups, bear gall group and positive drug group are all lower than that of model group (P<0.05), and the protein expression of GFAP of doze groups have no difference (P>0.05). The protein expression of NF-kb in doze groups, bear bile group, positive drug group are less than that of the model group (P<0.05). The protein expression of NF-Kb in high doze group, middle doze group and bear bile group are significantly less than that of the low dose group (P<0.05).
6.7days after Rats、ischemia-reperfusion, to detect the mRNA expression of GFAP and NF-kB in the brain organization, results shows:the mRNA expression of NF-kB of doze groups, bear gall group and positive drug group are all lower than that of model group (P<0.05), the mRNA expression of NF-kB of doze groups have no difference (P>0.05); the mRNA expression of GFAP of doze groups, bear gall group and positive drug group are all lower than that of model group (P<0.05), the mRNA expression of GFAP of doze groups have no difference (P>0.05).
Conclusions:
TongLuoHuaTan capsule and its active ingredients bear bile powder have a Significant neural protection, can reduce cerebral ischemia-reperfusion injury in rats with Brain tissue damage, which may due to its reduce the expression of TNF-alpha, NF-k b, ICAM-1, IL-1, R, IL-8, of GFAP and other related factors after ischemia-reperfusion injury in cerebral organization.
引文
[1]Allan SM, Tyrrel PJ, Rothwell NJ.Interleukin-1 and neuronal injury [J].Nat. Rev. Immunol. 2005,5(8); 629-640.
[2]Arumugam TV,Woodruff TM, Lathia JD,et al.Neuroprotection in stroke by complement inhibition and immunoglobulin therapy [J].Neuroscience,2009,158(3):1074-1089.
[3]Ferrari CC,Depino AM,Prada F,et al. Reversible demyelination,blood-brain barrier breakdown, and pronounced neutrophil recruitment induced by chronic IL-1 expression in the brain [J]. Am. J. Pathol.2004,165(5):1827-1837.
[4]Stammimvie D, Satoh K. Inflammatory mediator of cerebral endothelium:a role in ischemic brain inflammation [J]. Brain Pathol,2000,10(1):113-126.
[5]Depino A, Ferrari C, Pott CM, et al. Differential effects of interleukin-1 (3 on neurotoxcity, cytokine induction and glial reaction in specific brain regions[J]. J. Neuroimmunol,2005, 168 (1/2):96-110.
[6]Basu A, KradyJK, Levison SW.Interleukin-1:a master regulator of neuroinflammation [J]. J. Neurosci. Res.2004,8(2):151-156.
[7]Lin HW, Basu A, Drucknum C, et al. Astrogliosis is delayed in type 1 interleukin-1 receptor-null mice following a penetrating brain injury [J]. J. Neuroinflammation,2006,3: 15.
[8]向赞,董大翠,刘庆莹.脑缺血与白细胞介素6的变化[J].江汉大学学报,2005,23(2)：83.
[9]Jasna Kriz, Melanie Lalancette-Hebert. Inflammation, plasticity and real-time imaging after cerebral ischemia [J]. Acta. Neuropathol,2009,117(5):497.
[10]Loddick SA, Tumbtdl AV, Rothwell SJ. Cerebral interleukin-6 is neuroprotective during permanent focal cerebral ischemia in the rat [J].J. Cereb. Blood Flow Metab.1998,18 (2): 176-179.
[11]韩英,刘楠,陈荣华等.IL-8在大鼠脑缺血再灌注损伤中变化的实验研究[J].中国动脉硬化杂志,2005,12(3)：112.
[12]吴建华,方云祥.法舒地尔对大鼠脑缺血再灌注损伤炎症反应的影响[J].中国临床药理学与治疗学.2008,13(4)：377.
[13]Villa P, Triulzi S, Cavalieri B, et al. The interleukin-8(IL-8/CXCL8) receptor inhibitor reparixin improves neurological deficits and reduces long-term inflammation in permanent and transient cerebral ischemia in rats. [J]. Mol. Med.2007,13 (3/4):125-133
[14]Garau A, Bertini R, Colotta F, et al. Neuroprotection with the CXCL8 inhibitor repertaxin in transient brain ischemia [J]. Cytokine,2005,30 (3):125-131.
[15]Matsumoto T, Yokoi K, Mukaida N, et al. Pivotal role of interleukin-8 in the acute respiratory distress syndrome and cerebral reperfusion injury [J]. J. Leukoc. Biol.1997, 62:581-587.
[16]Strle K, Zhou jH, Shen WH, et al. Interleukin-10 in the brain [J]. Crit. Rev. Immunol.2001, 21 (5):427-449.
[17]Ooboshi H, Ibayashi S, Shichita T, et al. Postischemic gene transfer of interleukin-10 protects against both focal and global brain ischemia [J]. Circulation,2005,111(7): 913-919.
[18]Frenkel D, Huang Z, Maron R, et al. Neuroprotection by IL-10-producing MOG CD4+T cells following ischemic stroke [J]. J. Neurol. Sci.2005,233 (1/2):125-132.
[19]G.Ricci, L.Volpi, LPasquali, L.Petrozzi, et al. Astrocyte-neuron interactions in neurological disorders [J]. Journal of Biological Physics,2009,35 (4):317-336.
[20]Stammimvie D, Satoh K. Inflammatory mediators of cerebral endothelium:a role in ischemic brain intlammation [J]. Brain Pathol,2000,10 (1):113-126.
[21]Suzumura A, Ito A, Yoshikowa M. et al, Ibudilast suppresses TFN-a production by glial cells functional mainly as type III phosphodiesterase inhibitor in the CNS [J]. Brain Res. 1999,837 (1/2):203-212.
[22]Vilan N, Castillo J, Davalos A, et al. Proinflammatory cytokines and early neurological worsening in ischemic stroke [J]. Stroke,2000,31(10):2325-2329.
[23]Kimura H, Gules I, Meguro T, et al. Cytotoxicity of cytokines in cerebral microvascular endothelial cell [J]. Brain Bes.2003,990 (1-2):148-56.
[24]Kogakis, sawa Y, sano T, et al. Selectin on activated platelets enhances neutronphil endothelial adherence in myocardial reperfusion injury [J]. cardiovasc. Res.1999,43 (4): 968-973.
[25]李曼霞,董志.脑缺血再灌注时血脑屏障损伤的炎性机制研究进展[J].解放军药学学报,2007,23(1)：60-63.
[26]Huang J, Choudhri TF, Winfree CJ, et al. Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke[J]. Stroke,2000,31(12):3047-3053.
[27]Marlia SD, Springer TA. Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1(LFA-l) [J]. Cell.1987,51:813-819.
[28]Xu HL, Feng YP. Inhibitory effects of chiral 3-n-butylphthalide on inflammation following focal ischemic brain injury in rats [J]. Acta. Pharmacol. Sin.2000,21(5):433-438.
[29]Zhang RL,Chopp M,Li Y.et al.Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat[J].Neurology.1994,44(9):1747-1751
[30]Matsuo Y,Onodera H,Shiga Y,et al.Role of cell adhesion molecules in brain injury after transient middle cerebral artery occlusion in the rat[J].Brain Res.1994,656(2):344-352
[31]Sughrue ME, Mehra A, Connolly ES, et al. Anti-adhesion molecule strategies as potential neuroprotective agents in cerebral ischemia:A critical review of the literature [J]. Inflamm. Res.2004,53(10):497-508.
[32]Relton JK, Slosh KE, Frew EM, el al. Inhibition of a 4 integrin protects against transient focal cerebral ischemia in normotensive and hypertensive rats [J]. Stroke,2001,32(1): 199-205.
[33]Prestigiacomo CJ, Kim SC, Connolly ES, et al. CD18-mediated neutrophil recruitment contributes to the pathogenesis of reperfused but not nonreperfused stroke [J]. Stroke, 1999,30(5):1110-1117.
[34]Hess DC, Howard E, Cheng C, et al. Hypertonic mannitol loading of NF-k B transcription factor decoys in human brain microvascular endothelial cells blocks upregulation of ICAM-1 [J]. Stroke,2000,31(5):1179-1186.
[35]刘宗超,周官恩.NF-κB与脑缺血[J].中风与神经疾病杂志,2005,22(1)：88-90.
[36]He P, Zhang H, Zhu L, et al. Leukocyte-platelet aggregate adhesion and vascular permeability in intact microvessels:role of activated endothelial cells [J]. Am. J. Physiol. Heart Circ. Physiol.2006,291(2):591-599.
[37]Park TS, Gonzales ER, Gidday JM. Platelet-activating factor mediate ischemia-induced leukocyte-endothelial adherence in newborn pig brain [J]. J Cereb. Blood Flow Metab. 1999,19(4):417-424.
[38]Kassuya CA, Silvestre A, Menezes-de-Lima OJr, et al. Antiinflammatory and antiallodynic actions of the lignan niranthin isolated from Phyllanthus amarus:Evidence for interaction with platelet activating factor receptor [J]. Eur. J. Pharmacol,2006,546(1/3):182-188.
[39]Liu WC, Ding WL, Gu HY, et al. Lipopolysaccharide-induced cerebra inflammatory damage and the therapeutic effect of platelet activating factor receptor antagonist [J]. Neurosci Bull,2007,23(5):271-276.
[40]Strauss KI, Marini AM. Cyclooxygenase-2 inhibition protects cultured cerebellar granule neurons from glutamate-mediated cell death [J]. J. Neurotrauma,2002,19(5):627-638.
[41]Morioka N, Inoue A, Hanada T, et al. Nitric oxide synergistically potentiates interleukin-1 (3-induced increase of cyclooxygenase-2 mRNA levels, resulting in the faciliration of substance P release from primary afferent neurons:involvement of cGMP-independent mechanisms [J]. Neuropharmacology,2002,43(5):868-876.
[42]Zhang WP, Wei EQ, Mei RH, et al. Neuroprotective effect of ONO-1078, a leukotriene receptor antagonist, on focal cerebral ischemia in rats [J]. Acta. Pharmacol Sin.2002, 23(10):871-877.
[43]Ciceri P, Rabuffetti M, Monopoli A, et al. Production of leukotrienes in a model of focal cerebral ischaemia in the rat [J]. Br. J. Pharmacol,2001,133(8):1323-1329.
[44]Gasche Y, Soccal PM, Kanemitsu M, et al. Matrix metalloproteinases and diseases of the central nervous system with a special emphasis on ischemic brain [J]. Front Biosci.2006, 11:1289-1301.
[45]Lee SR, Lo EH. Induction of caspase-mediated cell death by matrix metalloproteinases in cerebral endothelial cells after hypoxia-reoxygenation [J]. J Cereb. Blood Flow Metab. 2004,24 (7):720-727.
[46]Lewen A, Matz P, Chart PH. Free radical pathways in CNS injury [J]. Neumtrauma,2000, 17 (10):871-890.
[47]Alto H, Aabo KT, Raivio KO. Biphasic ATP depletion caused by transient oxidative exposure is associated with apoptotic cell death in rat embryonal cortical neurons [J]. Pediatr. Res. 2002,52(1):40-45.
[48]Jassem W, Fuggle SV, Rela M, et al. The role of mitochondria in ischemia/reperfusion injury [J]. Transplantation,2002,73(4):493-439.
[49]李桂源,吴伟康,欧阳静萍等,病理生理学[M].北京,人民卫生出版社,2010,249-252
[50]Dalkara T, Moskowitz MA. The complex role of nitric oxide in the pathophysiology of focal ischemia [J].Brain Pathol,1994,4(1):49-57.
[51]Blomgren K, Hagberg H. Free radicals, mitochondria, and hypoxia-ischemia in the developing brain [J]. Free Radic. Biol. Med.2006,40(3):388-397.
[52]Gomi S, Karp AH. Regional alterations in an excitatory amino acid transporter, blood flow, and glucose metabolism after middle cerebral artery occlusion in the rat [J]. Exp. Brain Res.2000,130(4):521-528.
[53]lewen A, Matz P, Chan PH. Free radical pathways in CNS injury [J]. J Neurotrauma,2000, 17(10):871-890.
[54]李桂源,吴伟康,欧阳静萍等,病理生理学[M].北京,人民卫生出版社,2010.252-253
[55]李桂源,吴伟康,欧阳静萍等,病理生理学[M].北京,人民卫生出版社,2010.255-256
[56]秋红,王西明,王忠强等.体外模拟缺血再灌注诱导神经细胞线粒体功能改变的研究[J].卒中与神经疾病,2004,11(5)：271-274。
[57]Ishii HH, Gobe GC, Yoneyama J, et al. Role of P53, apoptosis, and cell proliferation in early stage Epstein-Barr virus positive and negative gastric carcinomas [J].Clin. Pathol.2004, 57(12):1306-1311.
[58]Lockshin RA. Programmed cell death:history and future of a concept [J]. Soc. Biol.2005, 199(3):169-173.
[59]Rosse T, Olivier R, Monney L, et al. Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c [J], Nature,1998,391(6666):496-499.
[60]Hotman p. Molecular regulation of neutrophil apoptosis and potential targets for therapeutic strategy against the inflammatory process [J]. Curr. Drug Targets Inflamm. Allergy,2004,3(1):1-9.
[61]Culmsee C, Plesnila N. Targeting Bid to prevent programmed cell death in neurons [J]. Biochem. Soc. Trans.2006,34:1334-1340.
[62]迟万好,曹明富,朱睦元,细胞凋亡的基因调控研究进展[J].杭州师范学院学报：自然科学版,2001,18(5)：46-47.
[63]Zhao H, Yenari MA, Cheng D, et al. Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity [J]. Neurochem,2003,85:1026-103.
[64]Hajnoczky G, Csordas G, Das S, et al. Mitochondrial calcium signaling and cell death: approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis [J]. Cell Calcium.2006,40(5-6):553-560.
[65]Verhaegen M, Bauer JA, Martin de la Vega C, et al. A novel BH3 mimetic reveals a mitogen-activated protein kinase-dependent mechanism of melanoma cell death controlled by p53 and reactive oxygen species [J]. Cancer Res.2006,66(23): 11348-11359.
[66]Longley DB, Allen WL, McDermott U, et al. The roles of thymidylate synthase and p53 in regulating Fas-mediated apoptosis in response to antimetabolites [J]. Clinical Cancer Research 2004; 10(10):3562-3571.
[67]Whitfield J, Neame SJ, Paquet L, et al. Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrcme c release [J]. Neuron,2001,29(3):629-643.
[68]Kindy MS, Carney JP, Dempsey RJ, et al. Ischemic induction of protooncogene expression in gerbil brain [J]. J. Mol. Neruosci.1991,2(4):217-228.
[69]黄旭晟,朱克.缺血性脑血管病基础研究新进展[J].国外医学(脑血管疾病分册),1995,3(1)：3-7.
[70]Hinoi E, Balcar VJ, Kuramoto, et al. Nuclear transcription factors in the hippocarupus [J], Prog. Neurobiol.2002,68(2):145-165.
[71]Ferrer I, Friguls B, Dalfo E, et al. Caspase-dependent and caspase-independent signalling of apoptosis in the penumbra following middle cerebral artery occlusion in the adult rat [J]. Neuropathol. Appl. Neurobiol.2003,29:472-481.
[72]王锐,成学恭,李光来.脑缺血再灌注与线粒体研究[J].医学综述.2002,8(7)：417-419.
[1]刘永刚,李芳君,王婧,等.银杏内酯B对大鼠脑缺血/再灌注损伤炎症反应的影响[J].中药材,2010,33(4)：578-580.
[2]李俊玲,牟凯,赵冬梅等.银杏叶提取物对大鼠脑缺血再灌注后Bcl-2、Bax蛋白和Caspase-3表达的影响[J].滨州医学院学报,2011,34(3)：187-188,191.
[3]闵珉,娆晨玲.Egb761对大鼠海马神经细胞缺血再灌注损伤保护作用的形态学研究[J].中国临床医学,2009,16(5)：686-688.
[4]段周芳,王金兰,娄季宇等.银杏叶提取物对大鼠脑缺血再灌注后GFAP和细胞凋亡的影响[J].中国实用神经疾病杂志,2011,14(3)：25-27.
[5]Cho JH, sung JH, Cho CH, et al. Gingko biloba Extract (EGb 761) prevents ischemic brain injury by activation of the Akt signaling pathway [J]. Am. J. chin. Med.2009,37(3): 547-555.
[6]姜丹,张乐,马军等.银杏叶注射液对脑缺血再灌注大鼠脑组织琥珀酸脱氢酶和肌酸激酶脑型同工酶活性的影响[J].中国临床保健杂志,2010,13(4)：389-391.
[7]唐婧妹,裴清华.三七总皂苷对大鼠脑缺血再灌注损伤的神经保护机制研究[J].中国实验方剂学杂志,2011,17(15)：210-213.
[8]刘旺华,李花,周小青,等.三七总皂苷对大鼠脑缺血再灌注海马细胞ca2+及线粒体膜电位的影响[J].中华中医药学刊,2009,z7(1)：99-101.
[9]闫俊岭,王云波,张华献等.三七皂苷Rg1对脑缺血再灌注损伤的保护作用[J].华西药学杂志,2007,22(2)：160-162.
[10]严永兴,粱丽贞,周智林.等.三七三醇皂苷对大鼠局灶脑缺血后梗死体积、细胞凋亡及caspase-3mRNA表达的影响[J].中国中医药科技,2010,17(3)：211-212.
[11]张秋玲,孙远标,王海英等.白花丹参对大鼠脑缺血再灌注致线粒体损伤及细胞凋亡的影响[J].中国病理生理杂志,2010,26(4)：725-729.DOI：10.3969/j.issn.1000-47182010.04.020.
[12]胡霞敏,周密妹,胡先敏等.丹参酮ⅡA对脑缺血再灌注大鼠脑损伤的保护作用及对能量代谢的影响[J].中国临床药学杂志,2006,15(3)：176-179.
[13]张景秋,赵喜庆,吉训明等.丹参抗脑缺血再灌注损伤的作用[J].河北医药,201032(24)：3501-3503.
[14]尹明华,徐晓虹,李怡佳.灯盏花素对缺血再灌注小鼠脑细胞凋亡的保护作用[J].中国药学杂志,2008,(3)：184-188.
[15]唐省三.灯盏花素对大鼠脑缺血再灌注后凋亡相关蛋白的干预[J].中国临床康复,2005,9(17)：130-131.
[16]朱丽娜,卢晓梅,赵成海,王巍,赵红.灯盏花素对脑缺血再灌注小鼠脑组织抗氧化酶的影响[J].中国医科大学学报,2005,34(5)：406-408.
[17]卢晓梅,赵红,张海鹏.灯盏花素对脑缺血再灌注小鼠明胶酶及血脑屏障通透性的影响[J].中国医科大学学报.2006,35(5)：481-483.
[18]何蔚,刘奕明,陈汇等.灯盏花素对大鼠局灶性脑缺血再灌注后脑水肿和中性粒细 胞浸润的影响[J].中国药理学与毒理学杂志,2004,18(3)：161-165.
[19]凌婧,邓文龙,张杰等.川芎油对大鼠脑缺血再灌注后脑组织ICAM-1、血浆TNF-α及ET的影响[J].中药药理与临床,2008,24(4)：32-34.
[20]阮琴.川芎挥发油川芎嗪对小鼠脑缺血再灌注损伤的保护作用[J].浙江中医杂志,2009,44(9)：642-643.
[21]李静,马兰,潘悦.川芎嗪对大鼠局灶性脑缺血再灌注损伤的保护作用[J].中药新药与临床药理,2008,19(6)；445-446.
[22]尹大维,陈正爱,潘晓明等.东川芎对大鼠脑缺血再灌注损伤的保护作用[J].延边大学医学学报,2008,31(3)：183-185.
[23]王巧云,吴峰阶.人参皂苷Rg1对局灶性脑缺血再灌注大鼠脑组织NOS活性及蛋白表达的影响[J].中国病理生理杂志,2011,27(12):2328-2332. DOI:10.3969/j. issn. 1000-4718.2011.12.017.
[24]胡霞敏,严常开,胡先敏等.人参皂苷Rg1对脑缺血再灌注损伤大鼠脑线粒体功能的影响[J].中国新药杂志,2006,15(7)：514-517.
[25]胡瑜,陈浩凡,臧林泉,等.人参皂苷Rb3对大鼠局灶性脑缺血损伤的保护作用[J].广东药学院学报,2008,4(5)：590-593.
[26]王坤芳,刘必旺,梁志刚等.乙酰葛根素对大鼠脑缺血再灌注VEGF表达的影响[J].光明中医,2011,26(6)：1122-1124DOI:10.3969/j. issn.1003-8914.2011.06. 021.
[27]王培源,王海萍,李光武等.葛根黄酮对大鼠脑缺血再灌注损伤的保护作用[J].中国中药杂志,2006,31(7)：577-579.
[28]许亮,陈春富.黄芪甲苷对大鼠脑缺血再灌注后小胶质细胞的影响[J].中华老年心脑血管病杂志,2011,(9)：847-850DOI:10.3969/j. issn.1009-0126.2011.09. 024.
[29]许亮,陈春富.黄芪甲苷预处理对脑缺血再灌注后外周型苯二氮卓受体表达的影响[J].中国神经精神疾病杂志,2011,37(6)：345-348.
[30]朱敏姿,徐彬,梁顺利等.黄芪注射液对脑缺血再灌注损伤大鼠MMP-9和IL-1β的影响[J].浙江中医杂志,2011,46(3)：207-208.
[31]闵小芬,李卫平,王绍斌等.黄芪提取物对局灶性脑缺血再灌注损伤的抗氧化及线粒体保护作用[J].中国药理学通报,2005,21(2)：216-219.
[32]赵燕玲,王宗仁.黄芪对脑缺血再灌注后神经细胞凋亡及Bcl-2蛋白表达的影响[J].中国临床康复,2005,9(33)：92-93.
[33]尹艳艳,李卫平,王绍斌等.黄芪提取物对大鼠局灶性脑缺血再灌注损伤后炎症因子及细胞凋亡的作用[J].中国药理学通报,2005,21(12)：1486-1489.
[34]孟新珍,王晓雯,蒋晓燕等.肉苁蓉总苷对清醒小鼠脑缺血再灌注损伤的保护作用[J].中国临床神经科学,2003,11(3)：239-242.
[35]孟新珍,王晓雯,蒋晓燕等.肉苁蓉总苷对清醒小鼠脑缺血再灌注致脑组织生化改变的影响[J].中华老年心脑血管病杂志,2004,6(1)：16.
[36]马仁强,陈健文,庞建新等.赤芍总苷对沙土鼠全脑缺血再灌注损伤的保护作用[J].第一军医大学学报,2005,25(4)：471-473.
[37]何延龙,周端,董六一等.赤芍总苷对大鼠局灶性脑缺血再灌注损伤的保护效果[J].中国临床康复,2006,10(39)：59-61.
[38]郭云良,沈卫,杜芳等.胡黄连苷Ⅱ对大鼠脑缺血再灌注损伤后TLR4及NFκB表达的影响[J].中国中西医结合杂志,2011,31(1)：58-61.
[39]薛荣亮,纪娜,高静等.茶多酚对大鼠全脑缺血再灌注损伤的影响[J].中华麻醉学杂志,2011,31(9)：1117-1119.DOI：10.3760/cma.j.issn.0254-1416.2011.09.025.
[40]丁涛,徐惠波,尚智等.注射用熊胆粉对大鼠大脑中动脉缺血再灌注损伤影响的研究[J].中国中医药科技,2008,15(3)：189-190.
[41]段晓慧,李秋云,郭棱棱等.黄芪注射液联合红花注射液对脑缺血再灌注大鼠NT-3的影响[J].中国中医急症,2010,19(6)：996-998.
[42]胡金玲,孟凡荣,董中国等.参附注射液对脑缺血再灌注大鼠bcl-2、p53表达的影响[J].中国老年学杂志,2011,31(9)：1621-1622.
[43]谢健,闵苏.参附注射液对局灶性脑缺血再灌注损伤大鼠血脑屏障通透性及神经功能的影响[J].重庆医科大学学报,2009,34(11)：1506-1509.
[44]江承平,刘福,李毅等.脑缺血再灌注损伤模型大鼠参附注射液干预后热休克蛋白70的表达[J].中国组织工程研究与临床康复,2011,15(41)：7661-7664DOI:10.3969/j . issn.1673-8225.2011.41.015.
[45]万敬枝,程梦琳,吴基良等.参附注射液对局灶性脑缺血再灌注大鼠脑组织NO、MDA含量和SOD活性的影响[J].中国中医急症,2004,13(6)：381-382.
[46]程梦琳,吴基良,罗德生等.参附注射液对局灶性脑缺血再灌注大鼠脑组织NO含量和NOS活性的影响[J].中国中医急症,2004,13(4)：234-235.
[47]张红波,代建峰,张宾辉等.醒脑静注射液对脑缺血再灌注氧化损伤的实验研究[J]浙江中医药大学学报,2006,30(3)：233-234,237.
[48]黄唯佳,陈寿权,王万铁等.《中国临床药理学与治疗学》2005年10期
[49]王万铁,陈寿权,王卫等.醒脑静注射液对实验性脑缺血-再灌注损伤中一氧化氮和内皮素水平的影响[J].中国中西医结合急救杂志,2002,9(6)：347-349.
[50]王万铁,陈寿权,王卫等.醒脑静注射液对实验性脑缺血及再灌注损伤中氧自由基水平的影响[J].中医药学刊,2004,22(3)：434-435.
[51]王万铁,陈寿权,徐正 等.醒脑静注射液对脑缺血-再灌注损伤家兔血清白介素-8的影响[J].温州医学院学报,2003,33(1)：1-3.
[52]赵雅宁,刘乐,安朝旺等.补阳还五汤通过抑制p38有丝分裂原激活蛋白激酶通路改善大鼠缺血性脑损伤[J].解剖学杂志,2011,34(1)：48-51.
[53]赵雅宁,吴晓光,李建民等.中药补阳还五汤对沙鼠脑缺血再灌注损伤及微循环障碍的治疗作用[J].四川大学学报(医学版),2010,41(1)：53-56.
[54]张运克,杨广华.补阳还五汤联合间充质干细胞移植对脑缺血再灌注损伤大鼠bFGF mRNA表达的影响[J].中医杂志,2011,52(7)：589-591.
[55]吴晓光,李强,郭园园等.补阳还五汤预处理对缺血再灌注损伤沙鼠脑组织血流量的影响[J].承德医学院学报,2011,28(2)：115-117.
[56]李建民,赵雅宁,安朝旺等.补阳还五汤对沙鼠前脑缺血再灌注损伤p38MAPK磷酸化、神经细胞凋亡的影响[J].中国老年学杂志,2009,29(23)：3051-3054.
[57]高剑峰,吕风华,王晓辉等.补阳还五汤对老龄大鼠脑缺血再灌注海马齿状回细胞增殖分化的影响[J].中国老年学杂志,2009,29(18)：2348-2350.
[58]宫健伟,叶蕾.补阳还五汤对脑缺血再灌注大鼠脑组织NO及NOS的影响[J].长春中医药大学学报,2010,26(6)：819-820.
[59]周荣峰,邓茜.芪棱汤对脑缺血再灌注损伤大鼠VEGF、CD34的影响[J].中国中医急症,2011,20(6)：922-923.
[60]周荣峰.芪棱汤对脑缺血再灌注损伤大鼠血脑屏障通透性及基质金属白酶-3表达的影响[J].中国中医急症,2010,19(9)：1554-1555,1585.
[61]周荣峰,邓茜,赵喜连等.芪棱汤对大鼠脑缺血再灌注损伤后MAP-2表达的影响[J].中国中医急症,2008,17(8)：1110-1111,1115.
[62]邓世芳,蒋红玉,张思为等.芪棱汤对大鼠脑缺血再灌注后兴奋性氨基酸的影响[J].中国中医急症,2011,20(4)：585-586.
[63]邓世芳,蒋红玉,张思为等.芪棱汤对大鼠脑缺血再灌注后热休克蛋白70的影响[J].中国中医急症,2010,19(12)：2096-2097.
[64]邓世芳,蒋红玉,张思为等.芪棱汤对大鼠脑缺血再灌注后一氧化氮的影响[J].吉林医学,2011,32(5)：835-836.
[65]朱海燕,迟蕾,徐冰等.清开灵注射液对血脑屏障模型通透性的影响[J].中国中医药信息杂志,2011,(9)：35-37DOI:10.3969/j. issn.1005-5304.2011.09.015
[66]高永红,袁拯忠,牛福玲等.新清开灵注射液对大鼠脑缺血再灌注损伤微血管内皮细胞黏附分子表达的影响[J].中华中医药杂志,2008,23(3)：197-200.
[67]庞春红,李澎涛,朱晓磊等.脑缺血-再灌注相关细胞因子表达的TNF-α损伤机制及清开灵的作用[J].世界中医药,2011,06(4)：343-346.
[68]王淑君,王万铁,熊建华等.红花注射液对脑缺血-再灌注损伤家兔血浆TXA2/PGI2水平的影响[J].中国现代应用药学,2003,20(2)：100-102.
[69]王淑君,王万铁,熊建华等.红花注射液对实验性脑缺血再灌注损伤中一氧化氮和内皮素的影响[J].中国急救医学,2003,23(5)：298-299.
[70]王淑君,王万铁,熊建华等.红花注射液对家兔脑缺血再灌注损伤时氧自由基变化的影响[J].温州医学院学报,2003,33(3)：153-155.
[71]冯洁,徐艳萍,裴保香等.复方丹参滴丸对酶的影响[J].实用诊断与治疗杂志,2006,20(6)：437-439.
[72]刘轲,李建生,杨歆科等.脑脉通对老龄大鼠脑缺血/再灌注微血管生成及FIk-1表达的影响[J].北京中医药大学学报,2011,34(1)：42-47.
[73]赵清超,胡久略,黄显章等.补肾醒脑方有效部位对脑缺血再灌注大鼠白细胞介素-1β和细胞间黏附分子-1表达的影响[J].中国实验方剂学杂志,2010,16(15)：136-139
[1]叶龙彬,奚涛,陈峰等.丹参酮ⅡA对大鼠局灶性脑缺血再灌注损伤的保护作用[J]中国药科大学学报,2004,35(3)：267-270.
[2]胡建鹏,王键,李净等.益气活血方对脑缺血再灌注损伤神经细胞凋亡及HSP70蛋白表达的影响[J].中国实验方剂学杂志,2005,11(2)：72-封三.
[3]汪远金,申国明,王钦茂等.川芎嗪对大鼠脑缺血再灌注损伤的保护作用[J].安徽中医学院学报,2000,19(1)：44-45.
[4]刘岑,韩小军,张华等.试从“毒损脑络”学说谈中风病精神障碍的病机特点[J].中国医药学报,2002,17(3)：188-189.
[5]邹忆怀.中风病发病阶段“毒损脑络”临床特征的初步分析[J].北京中医药大学学报,2008,(8)：509-511.
[6]Stammimvie D, Satoh K. Inflammatory mediators of cerebral endothelium:a role in ischemic brain intlammation [J]. Brain Pathol,2000,10 (1):113-126.
[7]Suzumura A, Ito A, Yoshikowa M. et al, Ibudilast suppresses TFN-α production by glial cells functional mainly as type Ⅲ phosphodiesterase inhibitor in the CNS [J]. Brain Res. 1999,837 (1/2):203-212.
[8]Vilan N, Castillo J, Davalos A, et al. Proinflammatory cytokines and early neurological worsening in ischemic stroke [J]. Stroke,2000,31(10):2325-2329.
[9]Xu HL, Feng YP. Inhibitory effects of chiral 3-n-butylphthalide on inflammation following focal ischemic brain injury in rats [J]. Acta. Pharmacol. Sin.2000,21(5):433-438.
[10]Zhang RL,Chopp M,Li Y.et al.Anti-ICAM-I antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat[J].Neurology.1994,44(9):1747-1751
[11]Matsuo Y,Onodera H,Shiga Y,et al.Role of cell adhesion molecules in brain injury after transient middle cerebral artery occlusion in the rat[J],Brain Res.1994,656(2):344-352.
[12]Ferrari CC,Depino AM,Prada F,et al. Reversible demyelination,blood-brain barrier breakdown, and pronounced neutrophil recruitment induced by chronic IL-1 expression in the brain [J]. Am. J. Pathol.2004,165(5):1827-1837.
[13]Stammimvie D, Satoh K. Inflammatory mediator of cerebral endothelium:a role in ischemic brain inflammation [J]. Brain Pathol,2000,10(1):113-126.
[14]Depino A, Ferrari C, Pott CM, et al. Differential effects of interleukin-1βon neurotoxcity, cytokine induction and glial reaction in specific brain regions[J]. J. Neuroimmunol,2005, 168 (1/2):96-110.
[15]韩英,刘楠,陈荣华等.IL-8在大鼠脑缺血再灌注损伤中变化的实验研究[J].中国动脉硬化杂志,2005,12(3)：112.
[16]吴建华,方云祥.法舒地尔对大鼠脑缺血再灌注损伤炎症反应的影响[J].中国临床药理学与治疗学.2008,13(4)：377.
[17]Hiscott J, Marois J, Garoufalis J, et al. Characterization of a functional NF-Kappa B site in the human interleukin I beta promoter:Evidence for a positive autoregulatory loop [J]. Mol. Cell. Boil.1993,13(10):6231-6240.
[18]Collins T, Read MA, Neish MZ, et al. Transcriptional regulation of endothelical cell adhesion molecules:NF-Kappa B and cytolin-in-ducible enhancers [J]. Faseb J, 1995,9(10):899-909.
[2]Arumugam TV,Woodruff TM, Lathia JD,et al.Neuroprotection in stroke by complement inhibition and immunoglobulin therapy [J].Neuroscience,2009,158(3):1074-1089.
[3]Ferrari CC,Depino AM,Prada F,et al. Reversible demyelination,blood-brain barrier breakdown, and pronounced neutrophil recruitment induced by chronic IL-1 expression in the brain [J]. Am. J. Pathol.2004,165(5):1827-1837.
[4]Stammimvie D, Satoh K. Inflammatory mediator of cerebral endothelium:a role in ischemic brain inflammation [J]. Brain Pathol,2000,10(1):113-126.
[5]Depino A, Ferrari C, Pott CM, et al. Differential effects of interleukin-1 (3 on neurotoxcity, cytokine induction and glial reaction in specific brain regions[J]. J. Neuroimmunol,2005, 168 (1/2):96-110.
[6]Basu A, KradyJK, Levison SW.Interleukin-1:a master regulator of neuroinflammation [J]. J. Neurosci. Res.2004,8(2):151-156.
[7]Lin HW, Basu A, Drucknum C, et al. Astrogliosis is delayed in type 1 interleukin-1 receptor-null mice following a penetrating brain injury [J]. J. Neuroinflammation,2006,3: 15.
[8]向赞,董大翠,刘庆莹.脑缺血与白细胞介素6的变化[J].江汉大学学报,2005,23(2)：83.
[9]Jasna Kriz, Melanie Lalancette-Hebert. Inflammation, plasticity and real-time imaging after cerebral ischemia [J]. Acta. Neuropathol,2009,117(5):497.
[10]Loddick SA, Tumbtdl AV, Rothwell SJ. Cerebral interleukin-6 is neuroprotective during permanent focal cerebral ischemia in the rat [J].J. Cereb. Blood Flow Metab.1998,18 (2): 176-179.
[11]韩英,刘楠,陈荣华等.IL-8在大鼠脑缺血再灌注损伤中变化的实验研究[J].中国动脉硬化杂志,2005,12(3)：112.
[12]吴建华,方云祥.法舒地尔对大鼠脑缺血再灌注损伤炎症反应的影响[J].中国临床药理学与治疗学.2008,13(4)：377.
[13]Villa P, Triulzi S, Cavalieri B, et al. The interleukin-8(IL-8/CXCL8) receptor inhibitor reparixin improves neurological deficits and reduces long-term inflammation in permanent and transient cerebral ischemia in rats. [J]. Mol. Med.2007,13 (3/4):125-133
[14]Garau A, Bertini R, Colotta F, et al. Neuroprotection with the CXCL8 inhibitor repertaxin in transient brain ischemia [J]. Cytokine,2005,30 (3):125-131.
[15]Matsumoto T, Yokoi K, Mukaida N, et al. Pivotal role of interleukin-8 in the acute respiratory distress syndrome and cerebral reperfusion injury [J]. J. Leukoc. Biol.1997, 62:581-587.
[16]Strle K, Zhou jH, Shen WH, et al. Interleukin-10 in the brain [J]. Crit. Rev. Immunol.2001, 21 (5):427-449.
[17]Ooboshi H, Ibayashi S, Shichita T, et al. Postischemic gene transfer of interleukin-10 protects against both focal and global brain ischemia [J]. Circulation,2005,111(7): 913-919.
[18]Frenkel D, Huang Z, Maron R, et al. Neuroprotection by IL-10-producing MOG CD4+T cells following ischemic stroke [J]. J. Neurol. Sci.2005,233 (1/2):125-132.
[19]G.Ricci, L.Volpi, LPasquali, L.Petrozzi, et al. Astrocyte-neuron interactions in neurological disorders [J]. Journal of Biological Physics,2009,35 (4):317-336.
[20]Stammimvie D, Satoh K. Inflammatory mediators of cerebral endothelium:a role in ischemic brain intlammation [J]. Brain Pathol,2000,10 (1):113-126.
[21]Suzumura A, Ito A, Yoshikowa M. et al, Ibudilast suppresses TFN-a production by glial cells functional mainly as type III phosphodiesterase inhibitor in the CNS [J]. Brain Res. 1999,837 (1/2):203-212.
[22]Vilan N, Castillo J, Davalos A, et al. Proinflammatory cytokines and early neurological worsening in ischemic stroke [J]. Stroke,2000,31(10):2325-2329.
[23]Kimura H, Gules I, Meguro T, et al. Cytotoxicity of cytokines in cerebral microvascular endothelial cell [J]. Brain Bes.2003,990 (1-2):148-56.
[24]Kogakis, sawa Y, sano T, et al. Selectin on activated platelets enhances neutronphil endothelial adherence in myocardial reperfusion injury [J]. cardiovasc. Res.1999,43 (4): 968-973.
[25]李曼霞,董志.脑缺血再灌注时血脑屏障损伤的炎性机制研究进展[J].解放军药学学报,2007,23(1)：60-63.
[26]Huang J, Choudhri TF, Winfree CJ, et al. Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke[J]. Stroke,2000,31(12):3047-3053.
[27]Marlia SD, Springer TA. Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1(LFA-l) [J]. Cell.1987,51:813-819.
[28]Xu HL, Feng YP. Inhibitory effects of chiral 3-n-butylphthalide on inflammation following focal ischemic brain injury in rats [J]. Acta. Pharmacol. Sin.2000,21(5):433-438.
[29]Zhang RL,Chopp M,Li Y.et al.Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat[J].Neurology.1994,44(9):1747-1751
[30]Matsuo Y,Onodera H,Shiga Y,et al.Role of cell adhesion molecules in brain injury after transient middle cerebral artery occlusion in the rat[J].Brain Res.1994,656(2):344-352
[31]Sughrue ME, Mehra A, Connolly ES, et al. Anti-adhesion molecule strategies as potential neuroprotective agents in cerebral ischemia:A critical review of the literature [J]. Inflamm. Res.2004,53(10):497-508.
[32]Relton JK, Slosh KE, Frew EM, el al. Inhibition of a 4 integrin protects against transient focal cerebral ischemia in normotensive and hypertensive rats [J]. Stroke,2001,32(1): 199-205.
[33]Prestigiacomo CJ, Kim SC, Connolly ES, et al. CD18-mediated neutrophil recruitment contributes to the pathogenesis of reperfused but not nonreperfused stroke [J]. Stroke, 1999,30(5):1110-1117.
[34]Hess DC, Howard E, Cheng C, et al. Hypertonic mannitol loading of NF-k B transcription factor decoys in human brain microvascular endothelial cells blocks upregulation of ICAM-1 [J]. Stroke,2000,31(5):1179-1186.
[35]刘宗超,周官恩.NF-κB与脑缺血[J].中风与神经疾病杂志,2005,22(1)：88-90.
[36]He P, Zhang H, Zhu L, et al. Leukocyte-platelet aggregate adhesion and vascular permeability in intact microvessels:role of activated endothelial cells [J]. Am. J. Physiol. Heart Circ. Physiol.2006,291(2):591-599.
[37]Park TS, Gonzales ER, Gidday JM. Platelet-activating factor mediate ischemia-induced leukocyte-endothelial adherence in newborn pig brain [J]. J Cereb. Blood Flow Metab. 1999,19(4):417-424.
[38]Kassuya CA, Silvestre A, Menezes-de-Lima OJr, et al. Antiinflammatory and antiallodynic actions of the lignan niranthin isolated from Phyllanthus amarus:Evidence for interaction with platelet activating factor receptor [J]. Eur. J. Pharmacol,2006,546(1/3):182-188.
[39]Liu WC, Ding WL, Gu HY, et al. Lipopolysaccharide-induced cerebra inflammatory damage and the therapeutic effect of platelet activating factor receptor antagonist [J]. Neurosci Bull,2007,23(5):271-276.
[40]Strauss KI, Marini AM. Cyclooxygenase-2 inhibition protects cultured cerebellar granule neurons from glutamate-mediated cell death [J]. J. Neurotrauma,2002,19(5):627-638.
[41]Morioka N, Inoue A, Hanada T, et al. Nitric oxide synergistically potentiates interleukin-1 (3-induced increase of cyclooxygenase-2 mRNA levels, resulting in the faciliration of substance P release from primary afferent neurons:involvement of cGMP-independent mechanisms [J]. Neuropharmacology,2002,43(5):868-876.
[42]Zhang WP, Wei EQ, Mei RH, et al. Neuroprotective effect of ONO-1078, a leukotriene receptor antagonist, on focal cerebral ischemia in rats [J]. Acta. Pharmacol Sin.2002, 23(10):871-877.
[43]Ciceri P, Rabuffetti M, Monopoli A, et al. Production of leukotrienes in a model of focal cerebral ischaemia in the rat [J]. Br. J. Pharmacol,2001,133(8):1323-1329.
[44]Gasche Y, Soccal PM, Kanemitsu M, et al. Matrix metalloproteinases and diseases of the central nervous system with a special emphasis on ischemic brain [J]. Front Biosci.2006, 11:1289-1301.
[45]Lee SR, Lo EH. Induction of caspase-mediated cell death by matrix metalloproteinases in cerebral endothelial cells after hypoxia-reoxygenation [J]. J Cereb. Blood Flow Metab. 2004,24 (7):720-727.
[46]Lewen A, Matz P, Chart PH. Free radical pathways in CNS injury [J]. Neumtrauma,2000, 17 (10):871-890.
[47]Alto H, Aabo KT, Raivio KO. Biphasic ATP depletion caused by transient oxidative exposure is associated with apoptotic cell death in rat embryonal cortical neurons [J]. Pediatr. Res. 2002,52(1):40-45.
[48]Jassem W, Fuggle SV, Rela M, et al. The role of mitochondria in ischemia/reperfusion injury [J]. Transplantation,2002,73(4):493-439.
[49]李桂源,吴伟康,欧阳静萍等,病理生理学[M].北京,人民卫生出版社,2010,249-252
[50]Dalkara T, Moskowitz MA. The complex role of nitric oxide in the pathophysiology of focal ischemia [J].Brain Pathol,1994,4(1):49-57.
[51]Blomgren K, Hagberg H. Free radicals, mitochondria, and hypoxia-ischemia in the developing brain [J]. Free Radic. Biol. Med.2006,40(3):388-397.
[52]Gomi S, Karp AH. Regional alterations in an excitatory amino acid transporter, blood flow, and glucose metabolism after middle cerebral artery occlusion in the rat [J]. Exp. Brain Res.2000,130(4):521-528.
[53]lewen A, Matz P, Chan PH. Free radical pathways in CNS injury [J]. J Neurotrauma,2000, 17(10):871-890.
[54]李桂源,吴伟康,欧阳静萍等,病理生理学[M].北京,人民卫生出版社,2010.252-253
[55]李桂源,吴伟康,欧阳静萍等,病理生理学[M].北京,人民卫生出版社,2010.255-256
[56]秋红,王西明,王忠强等.体外模拟缺血再灌注诱导神经细胞线粒体功能改变的研究[J].卒中与神经疾病,2004,11(5)：271-274。
[57]Ishii HH, Gobe GC, Yoneyama J, et al. Role of P53, apoptosis, and cell proliferation in early stage Epstein-Barr virus positive and negative gastric carcinomas [J].Clin. Pathol.2004, 57(12):1306-1311.
[58]Lockshin RA. Programmed cell death:history and future of a concept [J]. Soc. Biol.2005, 199(3):169-173.
[59]Rosse T, Olivier R, Monney L, et al. Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c [J], Nature,1998,391(6666):496-499.
[60]Hotman p. Molecular regulation of neutrophil apoptosis and potential targets for therapeutic strategy against the inflammatory process [J]. Curr. Drug Targets Inflamm. Allergy,2004,3(1):1-9.
[61]Culmsee C, Plesnila N. Targeting Bid to prevent programmed cell death in neurons [J]. Biochem. Soc. Trans.2006,34:1334-1340.
[62]迟万好,曹明富,朱睦元,细胞凋亡的基因调控研究进展[J].杭州师范学院学报：自然科学版,2001,18(5)：46-47.
[63]Zhao H, Yenari MA, Cheng D, et al. Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity [J]. Neurochem,2003,85:1026-103.
[64]Hajnoczky G, Csordas G, Das S, et al. Mitochondrial calcium signaling and cell death: approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis [J]. Cell Calcium.2006,40(5-6):553-560.
[65]Verhaegen M, Bauer JA, Martin de la Vega C, et al. A novel BH3 mimetic reveals a mitogen-activated protein kinase-dependent mechanism of melanoma cell death controlled by p53 and reactive oxygen species [J]. Cancer Res.2006,66(23): 11348-11359.
[66]Longley DB, Allen WL, McDermott U, et al. The roles of thymidylate synthase and p53 in regulating Fas-mediated apoptosis in response to antimetabolites [J]. Clinical Cancer Research 2004; 10(10):3562-3571.
[67]Whitfield J, Neame SJ, Paquet L, et al. Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrcme c release [J]. Neuron,2001,29(3):629-643.
[68]Kindy MS, Carney JP, Dempsey RJ, et al. Ischemic induction of protooncogene expression in gerbil brain [J]. J. Mol. Neruosci.1991,2(4):217-228.
[69]黄旭晟,朱克.缺血性脑血管病基础研究新进展[J].国外医学(脑血管疾病分册),1995,3(1)：3-7.
[70]Hinoi E, Balcar VJ, Kuramoto, et al. Nuclear transcription factors in the hippocarupus [J], Prog. Neurobiol.2002,68(2):145-165.
[71]Ferrer I, Friguls B, Dalfo E, et al. Caspase-dependent and caspase-independent signalling of apoptosis in the penumbra following middle cerebral artery occlusion in the adult rat [J]. Neuropathol. Appl. Neurobiol.2003,29:472-481.
[72]王锐,成学恭,李光来.脑缺血再灌注与线粒体研究[J].医学综述.2002,8(7)：417-419.
[1]刘永刚,李芳君,王婧,等.银杏内酯B对大鼠脑缺血/再灌注损伤炎症反应的影响[J].中药材,2010,33(4)：578-580.
[2]李俊玲,牟凯,赵冬梅等.银杏叶提取物对大鼠脑缺血再灌注后Bcl-2、Bax蛋白和Caspase-3表达的影响[J].滨州医学院学报,2011,34(3)：187-188,191.
[3]闵珉,娆晨玲.Egb761对大鼠海马神经细胞缺血再灌注损伤保护作用的形态学研究[J].中国临床医学,2009,16(5)：686-688.
[4]段周芳,王金兰,娄季宇等.银杏叶提取物对大鼠脑缺血再灌注后GFAP和细胞凋亡的影响[J].中国实用神经疾病杂志,2011,14(3)：25-27.
[5]Cho JH, sung JH, Cho CH, et al. Gingko biloba Extract (EGb 761) prevents ischemic brain injury by activation of the Akt signaling pathway [J]. Am. J. chin. Med.2009,37(3): 547-555.
[6]姜丹,张乐,马军等.银杏叶注射液对脑缺血再灌注大鼠脑组织琥珀酸脱氢酶和肌酸激酶脑型同工酶活性的影响[J].中国临床保健杂志,2010,13(4)：389-391.
[7]唐婧妹,裴清华.三七总皂苷对大鼠脑缺血再灌注损伤的神经保护机制研究[J].中国实验方剂学杂志,2011,17(15)：210-213.
[8]刘旺华,李花,周小青,等.三七总皂苷对大鼠脑缺血再灌注海马细胞ca2+及线粒体膜电位的影响[J].中华中医药学刊,2009,z7(1)：99-101.
[9]闫俊岭,王云波,张华献等.三七皂苷Rg1对脑缺血再灌注损伤的保护作用[J].华西药学杂志,2007,22(2)：160-162.
[10]严永兴,粱丽贞,周智林.等.三七三醇皂苷对大鼠局灶脑缺血后梗死体积、细胞凋亡及caspase-3mRNA表达的影响[J].中国中医药科技,2010,17(3)：211-212.
[11]张秋玲,孙远标,王海英等.白花丹参对大鼠脑缺血再灌注致线粒体损伤及细胞凋亡的影响[J].中国病理生理杂志,2010,26(4)：725-729.DOI：10.3969/j.issn.1000-47182010.04.020.
[12]胡霞敏,周密妹,胡先敏等.丹参酮ⅡA对脑缺血再灌注大鼠脑损伤的保护作用及对能量代谢的影响[J].中国临床药学杂志,2006,15(3)：176-179.
[13]张景秋,赵喜庆,吉训明等.丹参抗脑缺血再灌注损伤的作用[J].河北医药,201032(24)：3501-3503.
[14]尹明华,徐晓虹,李怡佳.灯盏花素对缺血再灌注小鼠脑细胞凋亡的保护作用[J].中国药学杂志,2008,(3)：184-188.
[15]唐省三.灯盏花素对大鼠脑缺血再灌注后凋亡相关蛋白的干预[J].中国临床康复,2005,9(17)：130-131.
[16]朱丽娜,卢晓梅,赵成海,王巍,赵红.灯盏花素对脑缺血再灌注小鼠脑组织抗氧化酶的影响[J].中国医科大学学报,2005,34(5)：406-408.
[17]卢晓梅,赵红,张海鹏.灯盏花素对脑缺血再灌注小鼠明胶酶及血脑屏障通透性的影响[J].中国医科大学学报.2006,35(5)：481-483.
[18]何蔚,刘奕明,陈汇等.灯盏花素对大鼠局灶性脑缺血再灌注后脑水肿和中性粒细 胞浸润的影响[J].中国药理学与毒理学杂志,2004,18(3)：161-165.
[19]凌婧,邓文龙,张杰等.川芎油对大鼠脑缺血再灌注后脑组织ICAM-1、血浆TNF-α及ET的影响[J].中药药理与临床,2008,24(4)：32-34.
[20]阮琴.川芎挥发油川芎嗪对小鼠脑缺血再灌注损伤的保护作用[J].浙江中医杂志,2009,44(9)：642-643.
[21]李静,马兰,潘悦.川芎嗪对大鼠局灶性脑缺血再灌注损伤的保护作用[J].中药新药与临床药理,2008,19(6)；445-446.
[22]尹大维,陈正爱,潘晓明等.东川芎对大鼠脑缺血再灌注损伤的保护作用[J].延边大学医学学报,2008,31(3)：183-185.
[23]王巧云,吴峰阶.人参皂苷Rg1对局灶性脑缺血再灌注大鼠脑组织NOS活性及蛋白表达的影响[J].中国病理生理杂志,2011,27(12):2328-2332. DOI:10.3969/j. issn. 1000-4718.2011.12.017.
[24]胡霞敏,严常开,胡先敏等.人参皂苷Rg1对脑缺血再灌注损伤大鼠脑线粒体功能的影响[J].中国新药杂志,2006,15(7)：514-517.
[25]胡瑜,陈浩凡,臧林泉,等.人参皂苷Rb3对大鼠局灶性脑缺血损伤的保护作用[J].广东药学院学报,2008,4(5)：590-593.
[26]王坤芳,刘必旺,梁志刚等.乙酰葛根素对大鼠脑缺血再灌注VEGF表达的影响[J].光明中医,2011,26(6)：1122-1124DOI:10.3969/j. issn.1003-8914.2011.06. 021.
[27]王培源,王海萍,李光武等.葛根黄酮对大鼠脑缺血再灌注损伤的保护作用[J].中国中药杂志,2006,31(7)：577-579.
[28]许亮,陈春富.黄芪甲苷对大鼠脑缺血再灌注后小胶质细胞的影响[J].中华老年心脑血管病杂志,2011,(9)：847-850DOI:10.3969/j. issn.1009-0126.2011.09. 024.
[29]许亮,陈春富.黄芪甲苷预处理对脑缺血再灌注后外周型苯二氮卓受体表达的影响[J].中国神经精神疾病杂志,2011,37(6)：345-348.
[30]朱敏姿,徐彬,梁顺利等.黄芪注射液对脑缺血再灌注损伤大鼠MMP-9和IL-1β的影响[J].浙江中医杂志,2011,46(3)：207-208.
[31]闵小芬,李卫平,王绍斌等.黄芪提取物对局灶性脑缺血再灌注损伤的抗氧化及线粒体保护作用[J].中国药理学通报,2005,21(2)：216-219.
[32]赵燕玲,王宗仁.黄芪对脑缺血再灌注后神经细胞凋亡及Bcl-2蛋白表达的影响[J].中国临床康复,2005,9(33)：92-93.
[33]尹艳艳,李卫平,王绍斌等.黄芪提取物对大鼠局灶性脑缺血再灌注损伤后炎症因子及细胞凋亡的作用[J].中国药理学通报,2005,21(12)：1486-1489.
[34]孟新珍,王晓雯,蒋晓燕等.肉苁蓉总苷对清醒小鼠脑缺血再灌注损伤的保护作用[J].中国临床神经科学,2003,11(3)：239-242.
[35]孟新珍,王晓雯,蒋晓燕等.肉苁蓉总苷对清醒小鼠脑缺血再灌注致脑组织生化改变的影响[J].中华老年心脑血管病杂志,2004,6(1)：16.
[36]马仁强,陈健文,庞建新等.赤芍总苷对沙土鼠全脑缺血再灌注损伤的保护作用[J].第一军医大学学报,2005,25(4)：471-473.
[37]何延龙,周端,董六一等.赤芍总苷对大鼠局灶性脑缺血再灌注损伤的保护效果[J].中国临床康复,2006,10(39)：59-61.
[38]郭云良,沈卫,杜芳等.胡黄连苷Ⅱ对大鼠脑缺血再灌注损伤后TLR4及NFκB表达的影响[J].中国中西医结合杂志,2011,31(1)：58-61.
[39]薛荣亮,纪娜,高静等.茶多酚对大鼠全脑缺血再灌注损伤的影响[J].中华麻醉学杂志,2011,31(9)：1117-1119.DOI：10.3760/cma.j.issn.0254-1416.2011.09.025.
[40]丁涛,徐惠波,尚智等.注射用熊胆粉对大鼠大脑中动脉缺血再灌注损伤影响的研究[J].中国中医药科技,2008,15(3)：189-190.
[41]段晓慧,李秋云,郭棱棱等.黄芪注射液联合红花注射液对脑缺血再灌注大鼠NT-3的影响[J].中国中医急症,2010,19(6)：996-998.
[42]胡金玲,孟凡荣,董中国等.参附注射液对脑缺血再灌注大鼠bcl-2、p53表达的影响[J].中国老年学杂志,2011,31(9)：1621-1622.
[43]谢健,闵苏.参附注射液对局灶性脑缺血再灌注损伤大鼠血脑屏障通透性及神经功能的影响[J].重庆医科大学学报,2009,34(11)：1506-1509.
[44]江承平,刘福,李毅等.脑缺血再灌注损伤模型大鼠参附注射液干预后热休克蛋白70的表达[J].中国组织工程研究与临床康复,2011,15(41)：7661-7664DOI:10.3969/j . issn.1673-8225.2011.41.015.
[45]万敬枝,程梦琳,吴基良等.参附注射液对局灶性脑缺血再灌注大鼠脑组织NO、MDA含量和SOD活性的影响[J].中国中医急症,2004,13(6)：381-382.
[46]程梦琳,吴基良,罗德生等.参附注射液对局灶性脑缺血再灌注大鼠脑组织NO含量和NOS活性的影响[J].中国中医急症,2004,13(4)：234-235.
[47]张红波,代建峰,张宾辉等.醒脑静注射液对脑缺血再灌注氧化损伤的实验研究[J]浙江中医药大学学报,2006,30(3)：233-234,237.
[48]黄唯佳,陈寿权,王万铁等.《中国临床药理学与治疗学》2005年10期
[49]王万铁,陈寿权,王卫等.醒脑静注射液对实验性脑缺血-再灌注损伤中一氧化氮和内皮素水平的影响[J].中国中西医结合急救杂志,2002,9(6)：347-349.
[50]王万铁,陈寿权,王卫等.醒脑静注射液对实验性脑缺血及再灌注损伤中氧自由基水平的影响[J].中医药学刊,2004,22(3)：434-435.
[51]王万铁,陈寿权,徐正 等.醒脑静注射液对脑缺血-再灌注损伤家兔血清白介素-8的影响[J].温州医学院学报,2003,33(1)：1-3.
[52]赵雅宁,刘乐,安朝旺等.补阳还五汤通过抑制p38有丝分裂原激活蛋白激酶通路改善大鼠缺血性脑损伤[J].解剖学杂志,2011,34(1)：48-51.
[53]赵雅宁,吴晓光,李建民等.中药补阳还五汤对沙鼠脑缺血再灌注损伤及微循环障碍的治疗作用[J].四川大学学报(医学版),2010,41(1)：53-56.
[54]张运克,杨广华.补阳还五汤联合间充质干细胞移植对脑缺血再灌注损伤大鼠bFGF mRNA表达的影响[J].中医杂志,2011,52(7)：589-591.
[55]吴晓光,李强,郭园园等.补阳还五汤预处理对缺血再灌注损伤沙鼠脑组织血流量的影响[J].承德医学院学报,2011,28(2)：115-117.
[56]李建民,赵雅宁,安朝旺等.补阳还五汤对沙鼠前脑缺血再灌注损伤p38MAPK磷酸化、神经细胞凋亡的影响[J].中国老年学杂志,2009,29(23)：3051-3054.
[57]高剑峰,吕风华,王晓辉等.补阳还五汤对老龄大鼠脑缺血再灌注海马齿状回细胞增殖分化的影响[J].中国老年学杂志,2009,29(18)：2348-2350.
[58]宫健伟,叶蕾.补阳还五汤对脑缺血再灌注大鼠脑组织NO及NOS的影响[J].长春中医药大学学报,2010,26(6)：819-820.
[59]周荣峰,邓茜.芪棱汤对脑缺血再灌注损伤大鼠VEGF、CD34的影响[J].中国中医急症,2011,20(6)：922-923.
[60]周荣峰.芪棱汤对脑缺血再灌注损伤大鼠血脑屏障通透性及基质金属白酶-3表达的影响[J].中国中医急症,2010,19(9)：1554-1555,1585.
[61]周荣峰,邓茜,赵喜连等.芪棱汤对大鼠脑缺血再灌注损伤后MAP-2表达的影响[J].中国中医急症,2008,17(8)：1110-1111,1115.
[62]邓世芳,蒋红玉,张思为等.芪棱汤对大鼠脑缺血再灌注后兴奋性氨基酸的影响[J].中国中医急症,2011,20(4)：585-586.
[63]邓世芳,蒋红玉,张思为等.芪棱汤对大鼠脑缺血再灌注后热休克蛋白70的影响[J].中国中医急症,2010,19(12)：2096-2097.
[64]邓世芳,蒋红玉,张思为等.芪棱汤对大鼠脑缺血再灌注后一氧化氮的影响[J].吉林医学,2011,32(5)：835-836.
[65]朱海燕,迟蕾,徐冰等.清开灵注射液对血脑屏障模型通透性的影响[J].中国中医药信息杂志,2011,(9)：35-37DOI:10.3969/j. issn.1005-5304.2011.09.015
[66]高永红,袁拯忠,牛福玲等.新清开灵注射液对大鼠脑缺血再灌注损伤微血管内皮细胞黏附分子表达的影响[J].中华中医药杂志,2008,23(3)：197-200.
[67]庞春红,李澎涛,朱晓磊等.脑缺血-再灌注相关细胞因子表达的TNF-α损伤机制及清开灵的作用[J].世界中医药,2011,06(4)：343-346.
[68]王淑君,王万铁,熊建华等.红花注射液对脑缺血-再灌注损伤家兔血浆TXA2/PGI2水平的影响[J].中国现代应用药学,2003,20(2)：100-102.
[69]王淑君,王万铁,熊建华等.红花注射液对实验性脑缺血再灌注损伤中一氧化氮和内皮素的影响[J].中国急救医学,2003,23(5)：298-299.
[70]王淑君,王万铁,熊建华等.红花注射液对家兔脑缺血再灌注损伤时氧自由基变化的影响[J].温州医学院学报,2003,33(3)：153-155.
[71]冯洁,徐艳萍,裴保香等.复方丹参滴丸对酶的影响[J].实用诊断与治疗杂志,2006,20(6)：437-439.
[72]刘轲,李建生,杨歆科等.脑脉通对老龄大鼠脑缺血/再灌注微血管生成及FIk-1表达的影响[J].北京中医药大学学报,2011,34(1)：42-47.
[73]赵清超,胡久略,黄显章等.补肾醒脑方有效部位对脑缺血再灌注大鼠白细胞介素-1β和细胞间黏附分子-1表达的影响[J].中国实验方剂学杂志,2010,16(15)：136-139
[1]叶龙彬,奚涛,陈峰等.丹参酮ⅡA对大鼠局灶性脑缺血再灌注损伤的保护作用[J]中国药科大学学报,2004,35(3)：267-270.
[2]胡建鹏,王键,李净等.益气活血方对脑缺血再灌注损伤神经细胞凋亡及HSP70蛋白表达的影响[J].中国实验方剂学杂志,2005,11(2)：72-封三.
[3]汪远金,申国明,王钦茂等.川芎嗪对大鼠脑缺血再灌注损伤的保护作用[J].安徽中医学院学报,2000,19(1)：44-45.
[4]刘岑,韩小军,张华等.试从“毒损脑络”学说谈中风病精神障碍的病机特点[J].中国医药学报,2002,17(3)：188-189.
[5]邹忆怀.中风病发病阶段“毒损脑络”临床特征的初步分析[J].北京中医药大学学报,2008,(8)：509-511.
[6]Stammimvie D, Satoh K. Inflammatory mediators of cerebral endothelium:a role in ischemic brain intlammation [J]. Brain Pathol,2000,10 (1):113-126.
[7]Suzumura A, Ito A, Yoshikowa M. et al, Ibudilast suppresses TFN-α production by glial cells functional mainly as type Ⅲ phosphodiesterase inhibitor in the CNS [J]. Brain Res. 1999,837 (1/2):203-212.
[8]Vilan N, Castillo J, Davalos A, et al. Proinflammatory cytokines and early neurological worsening in ischemic stroke [J]. Stroke,2000,31(10):2325-2329.
[9]Xu HL, Feng YP. Inhibitory effects of chiral 3-n-butylphthalide on inflammation following focal ischemic brain injury in rats [J]. Acta. Pharmacol. Sin.2000,21(5):433-438.
[10]Zhang RL,Chopp M,Li Y.et al.Anti-ICAM-I antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat[J].Neurology.1994,44(9):1747-1751
[11]Matsuo Y,Onodera H,Shiga Y,et al.Role of cell adhesion molecules in brain injury after transient middle cerebral artery occlusion in the rat[J],Brain Res.1994,656(2):344-352.
[12]Ferrari CC,Depino AM,Prada F,et al. Reversible demyelination,blood-brain barrier breakdown, and pronounced neutrophil recruitment induced by chronic IL-1 expression in the brain [J]. Am. J. Pathol.2004,165(5):1827-1837.
[13]Stammimvie D, Satoh K. Inflammatory mediator of cerebral endothelium:a role in ischemic brain inflammation [J]. Brain Pathol,2000,10(1):113-126.
[14]Depino A, Ferrari C, Pott CM, et al. Differential effects of interleukin-1βon neurotoxcity, cytokine induction and glial reaction in specific brain regions[J]. J. Neuroimmunol,2005, 168 (1/2):96-110.
[15]韩英,刘楠,陈荣华等.IL-8在大鼠脑缺血再灌注损伤中变化的实验研究[J].中国动脉硬化杂志,2005,12(3)：112.
[16]吴建华,方云祥.法舒地尔对大鼠脑缺血再灌注损伤炎症反应的影响[J].中国临床药理学与治疗学.2008,13(4)：377.
[17]Hiscott J, Marois J, Garoufalis J, et al. Characterization of a functional NF-Kappa B site in the human interleukin I beta promoter:Evidence for a positive autoregulatory loop [J]. Mol. Cell. Boil.1993,13(10):6231-6240.
[18]Collins T, Read MA, Neish MZ, et al. Transcriptional regulation of endothelical cell adhesion molecules:NF-Kappa B and cytolin-in-ducible enhancers [J]. Faseb J, 1995,9(10):899-909.