摘要
目的:急性缺血性中风是临床常见病、多发病,是严重威胁人类健康的主要疾病。其致残率高、复发率高已引起当前医务界广泛重视。中风病多见于中老年人,源于脏腑功能逐渐衰退,阴虚阳亢,阳化风动,加之人们生活水平的提高,饮食不节而伤及脾胃,脾失健运,聚湿生痰,痰郁化热,随肝风横窜经络,瘀血内阻,筋脉失养或肝风夹痰火上冲于脑,气血逆乱,血随气逆,蒙蔽清窍而发。因此我们采用通腑泻热法以釜底抽薪、挫其锐势,使腑气通、痰热去、九窍利。丹星通络汤是我科治疗缺血性中风的经验方,方中胆南星清热祛痰开窍,丹参活血通络,有效清除阻于脑络的痰浊和淤血。另大黄、川芎、槐花、三七、红花通腑泻热、行气活血,黄芪、黄芩、元参清热燥湿化痰。诸药相配共奏通腑泻热、祛痰开窍、逐瘀通络之功效。
且有研究表明天南星的提取物生物碱能抑制ADP和胶原引起的血小板聚集,对实验动物具有明显的扩张血管、降低血管阻力等作用。川芎能透过血脑屏障,具有扩张血管、改善脑循环和血液流变性和血液动力学、抗氧化等作用。丹参的有效成份主要为丹参酮,具有扩张血管、疏通微循环的功能,还可直接消除体内大量的氧自由基,使过氧化物歧化酶消耗降低,活性升高,并通过对微循环的调节,改善脑细胞对氧的利用。中西药结合,互相取长补短,明显提高了中风病的治疗效果。
细胞凋亡在脑缺血损伤中的作用日益受到重视,研究认为无论是急性的局灶性脑缺血还是短暂性脑缺血后的迟发性神经元死亡,都有神经细胞凋亡的参与,而凋亡在迟发性神经元死亡和半暗带的扩大中具有重要作用。在神经细胞凋亡过程中存在许多调控因素,利用这些调控因素可以阻止细胞凋亡进一步发展为坏死,这为临床治疗缺血性脑血管病提供新途径,因此应用药物阻止神经细胞凋亡成为当前国内外研究热点。新发现的一类抑凋亡基因家族( inhibitor of apoptosis protein, IAPs) ,其特殊的分子结构及抑制细胞凋亡的功能正日益引起人们的关注。发现IAPs与神经细胞凋亡、肿瘤等疾病有关,IAPs有可能作为靶蛋白为这些疾病的治疗开辟新路径。
方法:50只雄性Wistar大鼠,随机分为假手术组、脑缺血再灌注组、尼莫地平组、丹星通络汤小剂量组、丹星通络汤大剂量组各10只。尼莫地平组每日尼莫地平灌胃一次(2ml/100g),连续7天;丹星通络汤小剂量组(0.75ml/100g)、大剂量组(1.5ml/100g);假手术组和脑缺血再灌注组分别灌以2ml/100g的生理盐水。每日灌胃一次,连续7天。于第8天给药0.5 h后开始手术。采用大脑中动脉线栓法制作局灶脑缺血再灌注大鼠模型。大鼠局灶性脑缺血1h,然后进行再灌注。于再灌注24h后检测Survivin和Caspase-3的阳性细胞表达。
结果:
1.利用HE快速常规染色技术对大鼠脑缺血再灌注后脑组织超薄切片进行组织形态学观察:假手术组细胞结构正常;脑缺血再灌注组脑组织中均见神经细胞结构模糊,胞体肿胀,出现不同程度的核染色、核固缩、核溶解,核体不规则,有明显软化灶形成,周边可见中性粒细胞浸润;尼莫地平组、丹星通络汤小剂量组、丹星通络汤大剂量组神经细胞排列略紊乱,仍可见细胞皱缩和胞核固缩浓染现象,但程度较脑缺血再灌注组明显减轻,其中以尼莫地平组、丹星通络汤大剂量组尤为显著。
2.脑组织超薄切片免疫组化法观察Caspase-3、Survivin蛋白的表达水平:采用成组设多个样本比较的检验方法,五组大鼠在药物或替代药物作用下,发生脑缺血再灌注后丹星通络汤大、小剂量组与脑缺血再灌注组的Caspase-3和Survivin蛋白的表达有显著差异(P<0.05)。即:丹星通络汤对脑缺血再灌注后的脑组织Survivin表达有上调作用,对Caspase-3蛋白表达有下调作用。
3.血清中LDH值:脑缺血再灌注组血清LDH值均显著高于假手术组(P < 0.05);治疗组LDH值虽高于假手术组但均显著低于脑缺血再灌注组(P < 0.05)。
结论:丹星通络汤对脑缺血再灌注损伤具有一定的保护作用,可改善神经功能缺失,其作用机制可能与抑制Caspase-3蛋白合成,增加Survivin表达有关。
Objective:Acute cerebral ischemic stroke is clinical common disease and frequently encountered disease ,which is principal disease that threaten people’s health seriously.Stroke often occur on middle-aged and old-aged people. Because their entrails function decline gradually, adding their living standard is raising,they eat and drink without temperance ,finally all of these hurt their appetite, asthenic yin causeing predominant yang, dys-plenism, stagnation of phlegm converting into heat ,accompanying hepatic wind across veins and arteries,stagnant blood causing essential resisitance,muscle and vessel losing nutrition or hepatic wind with pyrophlegm upper punch brain,QI and blood inverse,bleeding resulting from adverse flow of QI, covering the upper orifices.So we can cure the sroke by suppressing this process.Danxing tongluo decoction(DXTLD) is a mixture of some herbs, such as Danshen, Dannanxing, Huaihua, Sanqi, Huangqi, etc. It has functions of cleaning away stagnated blood and heat, restoring normal functioning of the body to consolidate the constitution and resolving mass. Danshen, Dannanxing are the chief herbs of the dose, which can promote blood flow, deoppilate meridian, clean heat, eliminate sputum, etc. Huaihua, Sanqi, Chuanxiong, Honghua and Dahuang, are the secondary herbs of DXTLD. So the dose can efficaciously preclude the sputum stagnated blood and sputum blockaging in brain meridian. On account of appearance and substance are both to be cured, we can get a fine therapeutic effect by using it to cure the stroke.
Some research discover that natural extractive of Dannanxing can suppress platelet aggregation which caused by ADP and collogen,also can relax blood vessel visible and reduce vascular resistance. Chuanxiong can permeate blood-brain barrier ,relax blood vessel,improve cerebral ciculation and haemodynamics,resisit oxidation.The active constituent of Denshen is salviol.It can relax blood vessel and improve microcirculatory.It also can eliminate oxygen free radical directly,decrease consumption of peroxide dismutase,raise activity,then brain cell can use more oxygen.Combining tradicional Chinese medicine and western medicine can get a fine therapeutic effect.
People gradually pay attention to the function of apoptosis on cerebral ischemic stroke. Cellula nervosa apoptosis takes part in the delayed neuronal death which can coursed by both acute focal cerebral ischemia and transient cerebral ischemia.But apoptosis makes significant effect on delayed neuronal death and the semidarkness zonal .There so much control factor on the process of cellula nervosa apoptosis,which can prevent cellular necrosis from apoptosis.It provides a new way to cure cerebral ischemic stroke.So using medicine stop cellula nervosa apoptosis is a hot spot aroud the world.
There are all kinds of apoptotic profilin,but the new one is inhibitor of apoptosis protein(IAPs),which own special molecular constitution and the function that suppress apoptosis.IAPs is concerned with cellula nervosa apoptosis and tumor.As the target protein,IAPs maybe become the new method to cure the stroke.
Methods: Fifty healthy male Wistar rats were randomly assigned to 5 groups, 10 rats per group: sham operation group , ischemia/reperfusion (I/R) group, DXTLD high dosage group , DXTLD low dosage group and Nimodipine(NIMO) group. DXTLD groups were given to DXTLD at dose of 1.5ml/100g、0.75ml/100g;NIMO group at 2ml/100g,once a day. Saline were given to sham operation group and I/R group at 2ml/100g weight. After 7-days,the rats of all the groups except sham operation group were made into cerebral ischemia reperfusion injury models by thread embolism method. All the rats were killed and their brains were taken out after 1h ischemia and 24h reperfusion injury. The Caspase-3 expression and Survivin expression in brain tissue were measured with immune- ohistochemical method .
Results:
1.The ultrathin sections of brain tissue is made research about histomorphology by the common HE tacho-staining technique after rat cerebral ischemia and reperfusion:The group of sham operation group has normal cellular structure;The margin of focus of infection comparatively is distinct and the degree of cellular necrosis is more serious in the group of I/R group. The cells are obviously cutaneous dropsy. At the center of ischemic area we can find cellula nervosa necrosis, circum-cell diastem become broader, nucleus shrinkages, caryotheca fragments, chromato- spherite disappears, etc; While in the group of DXTLD high dosage group and NIMO group we can get the outcome that neuronal degeneration fairly light at ischemic region. Besides these, cells comparatively regular and full, and there are integrate living cells at the around of semidarkness area.
2. to observe the expression level of Caspase-3 gene and Survivin gene by the ultrathin sections of brain tissue and the method of immunohistochemistry technology : After the five groups rats had the medicine or substitute medicine and then disparity has significantly disparity between DXTLD high dosage group and I/R group(P<0.05). Videlicet : DXTLD could obviously increase the Survivin expression, decrease the Caspase-3 expression in cerebral cortex and hippocampus and relieve nerve cell injury.
3.Serumal LDH level of ischemia/reperfusion group were increased significantly compared with sham-operation group (P<0.05); Serumal LDH level of the treatment group were increased compared with the sham- operation group, but it decreased remarkably compared with the ischemia/ reperfusion group (P<0.05).
Conclusions: DXTLD can protect brain tissue of cerebral ischemia reperfusion injury and improve the nerve function. The mechanism may be related with the increasing of Survivin expression a decreasing of Caspase-3 expression.
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