萘非西坦对缺血性癫痫大鼠大脑组织的保护作用及其机制研究

发布时间：2018-04-25 15:31

本文选题：萘非西坦 + 脑缺血性癫痫模型　；参考：《南方医科大学》2016年博士论文

【摘要】：背景：脑卒中已超越肿瘤及心血管疾病,成为我国居民第一死亡原因,其中脑梗塞占大部分,约70-80%,随着我国人口老龄化加速,脑缺血发病人群逐年增大,且有发病年龄呈年轻化趋势。其致死及致残率非常高。癫痫发作是脑缺血的常见临床表现,在一些脑血管性疾病,诸如脑血管硬化狭窄、烟雾病、脑动静脉畸形,其早期表现或首发症状常为癫痫发作,均因为脑血管闭塞或发生盗血现象所导致,癫痫发作容易引发脑组织缺氧,加重病情,严重影响预后。尤其是新生儿,癫痫发作是血管性脑梗死的主要征兆及临床表现,且会迁延不愈。缺血性癫痫发生率日益增多,严重影响患者生活质量和社会功能,耗费了国家及社会巨大的人力和财力。故研究脑缺血性癫痫发作机制,寻找治疗新途径,能够带来巨大的社会及经济效益。癫痫是由于大脑神经元突发性异常放电,而导致短暂的大脑功能障碍的一种慢性疾病。由于异常放电的起始部位和传递方式的不同,癫痫发作的临床表现复杂多样,可表现为发作性运动、感觉、自主神经、意识及精神障碍。癫痫按病因分为两大类,即原发性癫痫和继发性癫痫。原发性癫痫的病因不明确,其与遗传因素关系密切,继发性癫痫的病因众多,为后天获得性病因。缺血性脑损伤是继发性癫痫发生的重要因素,然而其潜在的机制并不完全清楚,目前已有研究发现,脑缺血损伤后氧化应激反应、炎性反应、兴奋性神经传递与抑制性神经传递失衡以及离子通道功能的受损等机制在缺血性癫痫的发生中发挥重要调控作用。γ-氨基丁酸(GABA)是一种天然存在的非蛋白质氨基酸,是哺乳动物中枢神经系统中重要的抑制性神经传递物质,约30-40%的中枢神经突触部位以GABA为递质。在人体大脑皮质、海马、丘脑、基底神经节和小脑中起重要作用,并对机体的多种功能具有调节作用。在神经系统中,GABA转运体的两个亚型GAT-1和GAT-3是调节胞外GABA水平的主要因子。已有研究发现,GAT-1和GAT-3在新皮质、苍白球及海马区域中均起到调控GABA转运的作用,而GABA在大脑区域中的转运与癫痫的发生密切相关。癫痫患者发病过程中,常伴随脑脊液、局部神经元细胞及神经胶质细胞中氧化应激反应产物改变及促炎因子(Proinflammatory cytokines, PICs)的上升,与之相应的是,在大鼠缺血性癫痫模型中大脑顶叶/海马区/杏仁核组织中的促炎因子IL-1β、IL-6及TNF-α明显上调,另外进一步的研究发现在这些特殊的大脑区域,促炎因子IL-1β、IL-6及TNF-α的上调会改变GAT-1/GAT3的表达。萘非西坦(Nef iracetam, NEF)是一种吡咯烷酮衍生物的益智药物,具有兴奋神经的药理作用,能够增强海马区的神经元发育和修复,常用于颅脑损伤和缺血性脑损害患者提高其认知功能。文献报道萘非西坦主要通过以下机制促进神经系统功能康复：(1).N-甲基天冬氨酸受体(N-Methyl-D-aspartic Acid receptor)信号通路,通过激活该通路来提高记忆力,进而改善认知功能。(2).促代谢性谷氨酸受体-5 (metabotropic glutamate receptor-5)信号通路,Moriguchi等人在海马CA1区损害的大鼠模型研究中发现,萘非西坦通过激活该信号通路,促进记忆力的长时程增强而改善学习能力。(3).cAMP反应元件结合蛋白修饰作用,Han等人发现萘非西坦介导cAMP反应元件结合蛋白(cAMP response element-binding protein CREB)磷酸化,改善大鼠抑郁症状,改善认知能力。除了对神经系统具有益智作用外,已有研究发现萘非西坦可以减轻由杏仁核兴奋或化学药物(诸如藜芦定、谷氨酰胺等)诱导的癫痫症状。有学者研究发现小剂量萘非西坦即能够抑制电击诱导的大鼠癫痫发作,但治疗化学药物诱导的癫痫症状却效果欠佳。这可能与癫痫发作启动途径差异有关。因此萘非西坦可能是用于预防脑梗塞和(或)癫痫发作且提高认知功能的重要药物。对于机械阻断血管诱导的缺血性癫痫发作,尚未见文献报道萘非西坦治疗效果,据此,本课题以缺血性癫痫大鼠为模型,探讨萘非西坦对缺血性脑组织损伤及并发癫痫的保护作用及其作用机制。目的：通过建立大鼠缺血性癫痫模型,探讨萘非西坦对大脑顶叶/海马区/杏仁核组织的保护作用,以及GABA机制在萘非西坦抗脑组织损伤和癫痫中发挥的作用,为阐明萘非西坦的改善癫痫发作机制及其临床应用提供理论支持。方法：第一部分萘非西坦对缺血性脑组织损伤的保护作用研究1、将55只健康雄性SD大鼠(体重在250-300g之间)随机分为三组,第一组为假性手术组15只；第二组为缺血性癫痫模型组(对照组)20只；第三组为缺血性癫痫模型治疗组(实验组,即萘非西坦处理组)20只。采用血管内线栓闭塞法制作缺血性非惊厥性癫痫发作(nonconvulsive seizure, NCS)模型。以戊巴比妥((按体重45mg/kg)腹腔内注射麻醉后,先置大鼠俯卧,于大鼠头双侧额顶部(分别于前囟前lmm及后4mm,中线旁开3.5mm)对称性钻4个孔至皮层,植入四个不锈钢电极。在横窦上至人字缝后部之间置一参考电极。所有电极全部用多齿连接器固定于头部。脑电波由电极获取并传输至多参数显示仪和数字分析系统。缺血前30分钟至缺血后24小时之内对大鼠进行脑电图监测并描记结果,按先前Williams等人制定评判标准确定NCS波型,监测到NCS的频率即为该大鼠的实际NCSC发作次数。饲养3天后,按同样方法将大鼠麻醉,仰卧固定在手术台上,颈部正中切口,依次暴露并分离右侧颈总动脉(CCA)、颈外动脉(ECA)及其分支、颈内动脉分叉处,以血管夹暂时夹闭阻断ECA及其分支舌动脉和上颌动脉。于CCA分叉处近心侧做一切口,插入前端蘸有石蜡的3一0单股尼龙缝线,短暂夹闭翼腭动脉(PPA)以防误插,栓线经ICA入颅,插入深度约为20mm,至大脑前动脉近端,完全阻断大脑中动脉起始部的血供。手术过程采用激光多普勒流量计监测皮质脑血流量,如皮质脑血流量下降70%以上,以及术后1小时监测到癫痫波则定义为造模成功。假性手术组未做血管阻断,仅暴露血管后即原路缝合切口。实验组造模成功后即刻第一次腹腔内注射萘非西坦(以15 mg/ml的浓度按体重30mg/kg腹腔注射,12小时后再注射第二次,对照组相应地注射相同剂量的生理盐水。术后死亡者予以剔除,再随机补充。24小时后麻醉后断头取顶叶/海马脑/杏仁核脑组织,放于-80℃冰箱保存。2、根据脑电图记录各组大鼠癫痫发作的频率。3、组织损伤检测：(1)所取脑组织经甲醛固定、包埋、石蜡切片后进行HE染色观察顶叶/海马区/杏仁核组织大体形态、神经元损伤及炎性细胞浸润等。(2)采用ELISA法测定各组顶叶/海马区/杏仁核组织中TNF-α、IL-1β、 IL-6的含量,检测组织炎性反应程度。(3)采用比色法检测组织中MDA、GSH、GSSG的含量,观察组织氧化反应程度。(4)采用TUNEL染色法检测各组顶叶/海马区/杏仁核组织中神经元凋亡。第二部分GABA机制在萘非西坦抗脑组织损伤中发挥作用的研究1、研磨顶叶/海马区/杏仁核组织提取蛋白。免疫印迹(Western Blot)方法检测顶叶/海马区/杏仁核组织中GAT-1/GAT-3的蛋白含量。2、ELISA法测定各组顶叶/海马区/杏仁核组织中GABA的水平。结果：1、萘非西坦对缺血性癫痫大鼠脑组织损伤的保护作用(1)缺血处理后的对照组大鼠发生癫痫的频率明显较假性手术组升高,说明缺血处理成功诱导了大鼠癫痫,脑缺血是癫痫发作病因；而萘非西坦处理后,脑缺血性癫痫大鼠发生癫痫的频率较对照组明显降低,统计学比较差异显著(P0.05),说明萘非西坦可明显降低大鼠癫痫的发作频率。(2)组织形态学结果显示：假性手术组顶叶/海马区/杏仁核组织形态为正常状态,而缺血处理后的对照组大鼠顶叶/海马区/杏仁核组织形态明显受到损伤,可见明显的炎性细胞浸润、神经细胞出现溶解破坏和凋亡坏死、组织结构不完整等,萘非西坦处理后,由脑缺血引起的顶叶/海马区/杏仁核组织损伤明显减轻,可见组织形态相对完整、神经细胞凋亡坏死减少、且炎性细胞浸润明显减少。(3)假手术组大鼠顶叶/海马区/杏仁核组织中TNF-α、IL-1β、IL-6的含量处于基础水平；缺血处理后的对照组大鼠顶叶/海马区/杏仁核组织中TNF-α、 IL-1β、IL-6的含量较假性手术组明显升高,说明缺血引起大鼠顶叶/海马区/杏仁核组织的炎性反应；而萘非西坦处理后,脑缺血性癫痫大鼠顶叶/海马区/杏仁核组织中TNF-α、IL-1β、IL-6的含量较对照组明显降低,统计学比较有显著差异(P0.05),说明萘非西坦使得大鼠顶叶/海马区/杏仁核组织的炎性反应显著下降。(4)相对于假手术组大鼠顶叶/海马区/杏仁核组织中MDA、GSSG和GSH的表达水平,缺血处理后的对照组大鼠顶叶/海马区/杏仁核组织中MDA和GSSG的水平明显升高,而GSH的含量明显下降,说明缺血后大鼠顶叶/海马区/杏仁核组织中的氧化应激反应明显增强,而萘非西坦处理后可显著下调MDA和GSSG的水平,并提高GSH的含量。说明萘非西坦可以有效抑制缺血引起的顶叶/海马脑/杏仁核组织的氧化应激反应。(5) TUNEL染色结果显示,假手术组未见明显神经元凋亡,缺血对照组大鼠顶叶/海马区/杏仁核组织中神经元凋亡明显增加,而萘非西坦处理的实验组相较于缺血性癫痫对照组神经元凋亡数量明显下降。2、GABA机制在萘非西坦抗缺血性癫痫大鼠脑组织损伤中发挥的作用。(1)缺血处理后的对照组大鼠顶叶/海马区/杏仁核组织中GAT-1和GAT-3的表达水平较假性手术组明显升高,而脑缺血性癫痫模型使用萘非西坦处理后,顶叶/海马脑/杏仁核组织中GAT-1和GAT-3的表达水平较对照组均明显降低,统计学比较有显著差异(P0.05)。(2)缺血处理后的对照组大鼠顶叶/海马区/杏仁核组织中GABA水平较假性手术组明显下降,而脑缺血性癫痫模型使用萘非西坦处理后,顶叶/海马区/杏仁核组织中GABA的含量较对照组明显升高,统计学比较有显著差异(P0.05)。结论：本文采用血管内线栓闭塞法制作大鼠脑缺血性癫痫模型,并在手术后进行萘非西坦处理,分别统计假手术组、缺血性癫痫对照组及萘非西坦处理组大鼠术后癫痫发作频率,并对各组大鼠顶叶/海马区/杏仁核神经细胞损伤、炎性因子表达、氧化应激反应、GAT-1/GAT-3/GABA分子水平等进行检测和比较分析,得到以下结论：1、萘非西坦能明显减轻缺血性大鼠的癫痫发作频率。2、萘非西坦能明显减轻大鼠脑缺血性癫痫模型诱导的顶叶/海马区/杏仁核脑组织损伤。3、萘非西坦能明显减轻大鼠脑缺血性癫痫模型诱导的顶叶/海马区/杏仁核脑组织炎性反应。4、萘非西坦能明显减轻大鼠脑缺血性癫痫模型诱导的顶叶/海马区/杏仁核脑组织氧化应激。5、萘非西坦能明显减轻大鼠脑缺血性癫痫模型诱导的顶叶/海马区/杏仁核脑组织细胞坏死和凋亡。6、萘非西坦通过降低GAT-l/GAT-3及提高GABA的含量来降低大鼠脑缺血性癫痫模型的的癫痫发作频率。本研究通过机械阻断大脑中动脉成功制作大鼠脑缺血性癫痫模型,研究发现萘非西坦可减轻缺血性癫痫大鼠脑组织氧化应激反应(调节MDA、GSSG和GSH含量)和炎性反应(IL-1β、IL-6及TNF-α合成分泌增加),以及降低癫痫发作频率,且发现萘非西坦可能通过降低顶叶/海马区/杏仁核脑组织中GAT-1/GAT-3含量及提高突触间隙GABA分子的含量来降低大鼠脑缺血性癫痫模型诱导的癫痫发作频率,为阐明萘非西坦抗缺血性癫痫脑损伤的作用机制提供新思路,为萘非西坦应用于临床上治疗缺血性癫痫提供理论支持。
[Abstract]:Background: cerebral apoplexy has transcended tumor and cardiovascular disease, and it has become the first cause of death in our country. Cerebral infarction accounts for most of them, about 70-80%. With the accelerated aging of the population in China, the population of cerebral ischemia is increasing year by year, and the age of onset is younger. The incidence of death and disability is very high. Epileptic seizures are the common presence of cerebral ischemia. Bed performance, in some cerebrovascular diseases, such as cerebral arteriosclerosis stenosis, moyamoya disease, cerebral arteriovenous malformation, its early manifestations or first symptoms are often epileptic seizures, all caused by cerebral vascular occlusion or occurrence of blood theft, epileptic seizures can easily lead to brain tissue hypoxia, aggravate the condition, and seriously affect the prognosis. Especially in the newborn, epilepsy hair. It is the main symptom and clinical manifestation of vascular cerebral infarction, and it will not recover. The incidence of ischemic epilepsy is increasing, which seriously affects the quality of life and social function of the patients, and consumes the great human and financial resources of the state and society. Epilepsy is a chronic disease caused by sudden abnormal discharge of brain neurons, which leads to transient brain dysfunction. The clinical manifestations of epileptic seizures are complex and varied because of the difference in the starting position and delivery mode of abnormal discharge, which can be characterized by paroxysmal movement, sensation, autonomic nerves, consciousness and mental disorders. The etiology of primary epilepsy is divided into two categories, namely primary epilepsy and secondary epilepsy. The etiology of primary epilepsy is not clear. It is closely related to genetic factors. The cause of secondary epilepsy is multitudinous. The etiology of secondary epilepsy is acquired. Ischemic brain injury is an important factor in secondary epilepsy. However, the underlying mechanism is not completely clear. It is found that the mechanisms of oxidative stress, inflammatory response, excitatory neurotransmission and inhibitory neurotransmission imbalance, and impairment of the function of ion channels play an important role in the pathogenesis of ischemic epilepsy after cerebral ischemia. Gamma aminobutyric acid (GABA) is a natural non protein amino acid, a central mammalian God. Through an important inhibitory neurotransmitter in the system, the central nervous synapse of about 30-40% is GABA transmitter. It plays an important role in the human brain cortex, hippocampus, thalamus, basal ganglia and cerebellum, and regulates various functions of the body. In the nervous system, the two subtypes of the GABA transporter, GAT-1 and GAT-3, are regulatory cells. The main factors of external GABA level. It has been found that GAT-1 and GAT-3 play a role in the regulation of GABA transport in the neocortex, pallidus and hippocampus, and the transport of GABA in the brain region is closely related to the occurrence of epilepsy. The change of the stress reaction product and the rise of Proinflammatory cytokines (PICs), correspondingly, the proinflammatory factor IL-1 beta, IL-6 and TNF- alpha in the cerebral parietal lobe / hippocampus / amygdala tissue in the rat model of ischemic epilepsy are obviously up-regulated, and further studies have found that in these special brain regions, proinflammatory factor IL- is found. The up-regulation of 1 beta, IL-6 and TNF- alpha will change the expression of GAT-1/GAT3. Nef iracetam (NEF) is a beneficial drug of pyrrolidone derivatives. It has the pharmacological action of the excited nerve and can enhance the development and repair of neurons in the hippocampus. It is commonly used in patients with brain injury and ischemic brain damage. NNFA mainly promotes the functional rehabilitation of the nervous system through the following mechanisms: (1) the.N- methyl aspartate receptor (N-Methyl-D-aspartic Acid receptor) signaling pathway, which improves memory by activating the pathway, and then improves cognitive function. (2) the metabolic glutamate receptor -5 (metabotropic glutamate receptor-5) signaling pathway, Morig Uchi et al. In the rat model study of CA1 damage in the hippocampus, it was found that naphthalene enhanced the long term enhancement of memory by activating the signal pathway and improved learning ability. (3) the.CAMP reaction element combined with protein modification, and Han et al. Found the cAMP reaction element binding protein (cAMP response element-binding prote) mediated by naphthalene. In CREB) phosphorylation to improve the depressive symptoms of rats and improve cognitive ability. In addition to the beneficial effects of the nervous system, a study has found that naphthalene can relieve the epileptic symptoms induced by the amygdala excitation or chemical drugs (such as Veratrum, glutamine). Induced epileptic seizures were induced, but the treatment of chemical induced epileptic symptoms was not effective. This may be related to the difference in the onset of epileptic seizures. Therefore, naphthalene may be an important drug used to prevent cerebral infarction and / or seizures and improve cognitive function. In this study, the protective effect of naphthavan on ischemic brain tissue injury and epilepsy and its mechanism of action were investigated in this study. Objective: To explore the ischemic epilepsy model of rats and explore the effect of naphthavan on the brain parietal lobe / hippocampus / amygdala tissue. Protective effect, and the role of GABA mechanism in the anti brain tissue injury and epilepsy of naphthalene, to provide theoretical support for clarifying the mechanism and clinical application of naphthavan to improve epileptic seizures. Method: the first part of the study of the protective effect of naphthalene on ischemic brain tissue injury (1), 55 healthy male SD rats (weight in 250) Three groups were randomly divided into three groups, the first group was 15 of the pseudooperation group, the second group was the ischemic epilepsy model group (control group) 20, and the third group was the ischemic epilepsy model treatment group (experimental group, that is, naphthalene treatment group) 20. The ischemic non convulsive seizure was made by the endovascular occlusion (nonconvulsive seizure, N). CS) model. After intraperitoneal injection of pentobarbital ((according to body weight 45mg/kg), the rats were placed on the prone position, at the top of the head of the rat (at the anterior fontanelle, LMM and post 4mm, the middle line 3.5mm), and the four stainless steel electrodes were implanted into the cortex, and a reference electrode was placed between the transverse sinus and the posterior part of the human character. All the electrodes were used. The multi tooth connector was fixed on the head. The EEG was obtained by the electrode and transmitted to the multi parameter display instrument and the digital analysis system. The electroencephalogram monitoring and tracing results were carried out within 30 minutes before ischemia and within 24 hours after ischemia, and the NCS wave was determined by the previous Williams et al. The frequency of monitoring NCS was the actual N of the rat. The number of CSC episodes. After 3 days, the rats were anesthetized in the same way. The supine was fixed on the operating table and the neck was incisive to expose and separate the right common carotid artery (CCA), the external carotid artery (ECA) and its branch, the fork of the internal carotid artery, and temporarily clamp and block the ECA, the branch of the tongue and the maxillary artery by the clamp, and the proximal part of the CCA branch. 3 1 0 single strand nylon sutures with paraffin were inserted into the front end, and the pterygopalatine artery (PPA) was temporarily closed to prevent misinsertion. The thrombus line was inserted into the skull by ICA, and the insertion depth was about 20mm, to the proximal part of the anterior cerebral artery, which completely blocked the blood supply in the beginning of the middle cerebral artery. The laser Doppler flowmeter was used to monitor the cortical brain blood flow, such as the cortex brain. The blood flow decreased more than 70%, and the monitoring of epileptic wave at 1 hours after the operation was defined as a successful model. The artificial operation group did not do the blood vessel blocking, only after the exposure of the blood vessels was the primary suture incision. The first time in the experimental group was the first intraperitoneal injection of naphthalene (with a concentration of 15 mg/ml of 30mg/kg intraperitoneal injection, and then reinjected after 12 hours. " At the second time, the control group was injected with the same dose of physiological saline. The patients who died after the operation were eliminated, and then the brain tissue of the parietal lobe / hippocampus / amygdala were taken after.24 hours after anesthesia, and.2 was stored at -80 centigrade refrigerator. The frequency of epileptic seizures in each group was recorded by electroencephalogram (.3) and tissue damage detection: (1) the brain tissue was taken. After fixed, embedded and paraffin section, HE staining was used to observe the gross morphology of the parietal / hippocampus / amygdala tissue, neuron damage and inflammatory cell infiltration. (2) the content of TNF- a, IL-1 beta, IL-6 in the parietal / hippocampus / amygdala tissues of each group were measured by ELISA method, and the degree of inflammatory response in the tissue was detected. (3) the colorimetric assay was used to detect MD in the tissue. The content of A, GSH, GSSG and the degree of tissue oxidation. (4) TUNEL staining was used to detect neuronal apoptosis in the parietal / hippocampus / amygdala tissues. The second part of the GABA mechanism in the anti brain tissue injury of naphthalene 1, the lapping parietal lobe / hippocampus / amygdala tissue extraction protein. Western blot (Western Blot) side The protein content of GAT-1/GAT-3 in the parietal / hippocampus / amygdala tissues was detected by the method of.2, and the level of GABA in the parietal lobe / hippocampus / amygdala tissue in each group was measured by ELISA. Results: 1, the protective effect of naphthalene on the brain damage in the ischemic epileptic rats (1) the frequency of epilepsy in the control group after the ischemic treatment was significantly more than that of the pseudooperation The group increased, indicating that ischemic treatment successfully induced epilepsy in rats and cerebral ischemia was the cause of epileptic seizures. After naphthalene treatment, the frequency of epileptic seizures in rats with cerebral ischemic epilepsy was significantly lower than that in the control group (P0.05), indicating that naphthalene could significantly reduce the frequency of epileptic seizures in rats. (2) histomorphology The results showed that the tissue morphology of the parietal lobe / hippocampus / amygdala in the artificial operation group was normal, while the tissue morphology of the parietal lobe / hippocampus / amygdala in the control group after the ischemic treatment was obviously damaged, the obvious inflammatory cell infiltration, the dissolving and necrosis of the nerve cells, the incomplete tissue structure, and so on, were found in the control group. After treatment, the injury of the parietal / hippocampus / amygdala tissue caused by cerebral ischemia was significantly reduced, the morphology of the tissue was relatively complete, the apoptosis and necrosis of the nerve cells decreased, and the infiltration of inflammatory cells decreased significantly. (3) the content of TNF- a, IL-1 beta and IL-6 in the parietal / hippocampus / amygdala tissues of the sham operation group was at the basic level; after the ischemic treatment The content of TNF- alpha, IL-1 beta and IL-6 in the parietal lobe / hippocampus / amygdala of the control group was significantly higher than that in the pseudooperative group, indicating that ischemia caused the inflammatory response in the parietal / hippocampus / amygdala tissues in rats, while the content of TNF- a, IL-1 beta, IL-6 in the parietal / hippocampus / amygdala tissues of the ischemic epileptic rats was compared with that of naphthalene. The control group decreased significantly (P0.05), indicating that the inflammatory response of the parietal / hippocampus / amygdala in the rats was significantly reduced by naphthacan. (4) the expression of MDA, GSSG and GSH in the parietal / hippocampus / amygdala tissues of the sham operation group was flat, and the parietal / hippocampus / apricot in the control group after the ischemic treatment. The levels of MDA and GSSG in the kernel increased significantly, while the content of GSH decreased significantly, indicating that the oxidative stress in the parietal / hippocampus / amygdala tissues of rats after ischemia was significantly enhanced, while naphthalene treatment could significantly reduce the level of MDA and GSSG and increase the content of GSH. The oxidative stress reaction of the parietal / hippocampal / amygdala tissues. (5) TUNEL staining showed that there was no obvious neuronal apoptosis in the sham operation group, and the apoptosis in the parietal / hippocampus / amygdala tissues of the rats of the ischemic control group was significantly increased, while the number of apoptotic neurons in the naphthalene treated group was significantly higher than that of the ischemic epilepsy control group. The effect of.2 and GABA mechanism on the brain tissue injury of ischemic epileptic rats was played by the mechanism of naphthacan. (1) the expression level of GAT-1 and GAT-3 in the parietal / hippocampus / amygdala tissues of the control group was significantly higher than that of the pseudooperative group, while the cerebral ischemic epileptic model was treated with naphthacan, the parietal lobe / hippocampus / apricot. The expression levels of GAT-1 and GAT-3 in the kernels were significantly lower than those in the control group (P0.05). (2) ischemic treatment.

【学位授予单位】：南方医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R743.3

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