【摘要】：背景與目的 隨著科技的發(fā)展，人民生活水平的提高，人們壽命的延長(zhǎng)，生活節(jié)奏的加快以及環(huán)境污染的加重，腦卒中發(fā)病率和致殘率程逐年增高的趨勢(shì)。腦卒中不僅可以引起偏癱、偏身感覺(jué)異常、偏盲、失語(yǔ)、實(shí)用等一系列神經(jīng)系統(tǒng)缺失樣癥狀體征，還可以引起認(rèn)知功能障礙以及與心理、生理、社會(huì)因素綜合作用引起患者情緒低落、自罪自責(zé)、興趣減少為主要表現(xiàn)的卒中后抑郁（post strokedepression，PSD)。PSD是多種因素綜合作用的結(jié)果，無(wú)論國(guó)內(nèi)還是國(guó)外，其發(fā)病率普遍較高，國(guó)外報(bào)道多集中在30%-50%之間，國(guó)內(nèi)報(bào)道的差異性較大，分布在34.2%-79%之間。PSD不僅影響腦卒中患者神經(jīng)功能的恢復(fù)，還給患者給家屬帶來(lái)額外的經(jīng)濟(jì)及精神負(fù)擔(dān)，因此PSD的正規(guī)治療不可忽視。5-HT再攝取抑制劑（selective serotonin reuptake inhibitors,SSRIs）可以改善PSD患者的抑郁狀態(tài)、加快神經(jīng)功能恢，加之其較少的消化道、頭疼及QT間期延長(zhǎng)等不良反應(yīng)，在臨床中最常用于老年P(guān)SD患者，，然而該藥對(duì)腦卒中患者認(rèn)知功能的影響眾說(shuō)紛紜，因此探討SSRIs對(duì)慢性腦缺血患者認(rèn)知功能的影響及其作用機(jī)制顯得極為迫切和重要。 慢性腦缺血是中樞神經(jīng)系統(tǒng)一種常見(jiàn)的病理狀態(tài)。慢性腦缺血或腦灌注不足常伴發(fā)于血管性癡呆（Vascular dementia，VD)、腦動(dòng)脈硬化、Binswanger病、Alzheimer病以及動(dòng)靜脈畸形等多種腦血管疾病的病理過(guò)程中,發(fā)病早期以認(rèn)知功能損害為主要表現(xiàn),最終可能導(dǎo)致持久或進(jìn)展性認(rèn)知與神經(jīng)功能障礙。大量研究表明5-羥色胺再攝取抑制劑（SSRIs）對(duì)興奮性氨基酸，氧化應(yīng)激及缺血缺氧等多種機(jī)制造成的腦損傷有保護(hù)作用。Steckler T等學(xué)者認(rèn)為2-VO大鼠學(xué)習(xí)能力的下降與額葉皮質(zhì)和海馬5-羥色胺的遲發(fā)性下降有關(guān)。因此我們推測(cè)，5-羥色胺再攝取抑制劑可能改善慢性腦缺血患者的認(rèn)知功能。艾司西酞普蘭是一種強(qiáng)效的5-羥色胺再攝取抑制劑類(lèi)抗抑郁藥(SSRI)，與其同類(lèi)藥物相比，對(duì)5-HT受體選擇性更高，起效迅速，被廣泛用于老年抑郁和卒中后抑郁的預(yù)防與治療。Choong Hyun Lee等人證實(shí)了30mg/kg艾司西酞普蘭后處理缺血再灌注的大鼠，可以促進(jìn)海馬CA1區(qū)BDNF的表達(dá)，并且保護(hù)海馬CA1區(qū)由缺血誘導(dǎo)的神經(jīng)元死亡，而對(duì)于慢性腦缺血所致的認(rèn)知障礙影響研究國(guó)內(nèi)外尚未見(jiàn)報(bào)道。本實(shí)驗(yàn)采用2VO模型大鼠，應(yīng)用水迷宮、Western blot以及高爾基染色觀察艾司西酞普蘭對(duì)慢性腦缺血大鼠認(rèn)知功能及海馬區(qū)BDNF含量的影響。 材料與方法 SD大鼠（健康雄性）240只，約24周齡，體重約450g，由鄭州大學(xué)醫(yī)學(xué)院實(shí)驗(yàn)動(dòng)物供應(yīng)中心提供，隨機(jī)分為假手術(shù)組、模型組和實(shí)驗(yàn)組，選給藥后1、2、4、8周四個(gè)時(shí)間點(diǎn)，每組20只。實(shí)驗(yàn)組為2VO模型大鼠每天給予30mg/kg·dESC灌胃，采用雙側(cè)頸總動(dòng)脈永久性阻斷法（2VO）建立慢性腦缺血模型，選給藥滿(mǎn)1、2、4、8周四個(gè)時(shí)間點(diǎn)，通過(guò)Morris水迷宮檢測(cè)各組大鼠的認(rèn)知功能，Western blot檢測(cè)大鼠海馬區(qū)BDNF的表達(dá)，高爾基染色觀察神經(jīng)元樹(shù)突長(zhǎng)度、分支及樹(shù)突棘密度的變化。 結(jié)果 1．ESC對(duì)慢性腦缺血大鼠認(rèn)知功能的影響 假手術(shù)組大鼠個(gè)時(shí)間點(diǎn)比較逃避潛伏期無(wú)統(tǒng)計(jì)學(xué)差別（P0.05）：同一觀察點(diǎn)，與對(duì)照組相比實(shí)驗(yàn)組大鼠逃避潛伏期顯著縮短（P0.05），實(shí)驗(yàn)組與模型組的逃避潛伏期均較假手術(shù)組顯著延長(zhǎng)（P0.05）。 2．ESC對(duì)慢性腦缺血大鼠海馬區(qū)BDNF表達(dá)水平的影響 同一觀察點(diǎn)，實(shí)驗(yàn)組和模型組海馬區(qū)BDNF含量較假手術(shù)組減少(P0.05),實(shí)驗(yàn)組海馬區(qū)BDNF含量較模型組增多（P0.05)。 3．ESC對(duì)慢性腦缺血大鼠海馬區(qū)大錐體細(xì)胞形態(tài)的影響 模型組和實(shí)驗(yàn)組大鼠海馬CA1區(qū)大錐體細(xì)胞樹(shù)突長(zhǎng)度、分支及樹(shù)突棘密度較假手術(shù)組明顯減少(P0.05)，實(shí)驗(yàn)組海馬CA1區(qū)大錐體細(xì)胞樹(shù)突分支及長(zhǎng)度、樹(shù)突棘密度較模型組明顯增多（P0.05）。 結(jié)論 艾司西酞普蘭能明顯延緩慢性腦缺血大鼠認(rèn)知功能障礙的進(jìn)展,其機(jī)制可能是通過(guò)促進(jìn)BDNF表達(dá)從而改善學(xué)習(xí)記憶能力。
[Abstract]:Background and purpose
With the development of science and technology, the improvement of people's living standard, the prolongation of life life, the quickening of the rhythm of life and the aggravation of environmental pollution, the incidence of stroke and the rate of disability are increasing year by year. Stroke can not only cause hemiplegia, abnormal feeling of deviation, hemiinas, loss of speech, and practicality, but also a series of symptoms and signs of lack of nerve system. Post strokedepression (PSD).PSD, which can cause cognitive dysfunction and psychological, physiological and social factors to cause depression, self reproach and decrease of interest (PSD), is the result of a combination of various factors. Between 30%-50%, the difference in domestic reports is larger. The distribution of.PSD between 34.2%-79% not only affects the recovery of neural function of stroke patients, but also brings extra economic and spiritual burden to the family members, so the regular treatment of PSD can not ignore the.5-HT reuptake inhibitor (selective serotonin reuptake inhibitors, SSRIs) can be changed. The depressive state of patients with good PSD, quickening the nerve function restorer, combined with its less digestive tract, headache and prolongation of QT interval, is most commonly used in the elderly patients with PSD. However, the influence of the drug on cognitive function of stroke patients is different, so the effect of SSRIs on cognitive function of patients with chronic cerebral ischemia and its action machine are discussed. The system is very urgent and important.
Chronic cerebral ischemia is a common pathological state of the central nervous system. Chronic cerebral ischemia or insufficient cerebral perfusion is often associated with vascular dementia (Vascular dementia, VD), cerebral arteriosclerosis, Binswanger's disease, Alzheimer disease, and arteriovenous malformation, and the early onset of cognitive impairment is the main table. A large number of studies have shown that the 5- hydroxytryptamine reuptake inhibitor (SSRIs) has protective effects on brain damage caused by various mechanisms such as excitatory amino acids, oxidative stress and ischemic anoxia..Steckler T and other scholars believe that the learning ability of 2-VO rats decreases with the frontal cortex and the sea. Therefore, we speculate that the 5- serotonin reuptake inhibitor may improve the cognitive function of patients with chronic cerebral ischemia. Essicitalopram is a powerful 5- serotonin reuptake inhibitor type antidepressant (SSRI), which is more selective to 5-HT receptor, rapid and widely used than its similar drugs, as compared with its similar drugs. The prevention and treatment of depression and post-stroke depression in the elderly.Choong Hyun Lee et al. Confirmed that the rats after 30mg/kg isisalopram treatment with ischemia-reperfusion can promote the expression of BDNF in the CA1 region of the hippocampus, and protect the neuronal death induced by ischemia in the hippocampal CA1 region, and the effect of the cognitive impairment on chronic cerebral ischemia The 2VO model rats were used to observe the effects of Ai Sciplan on cognitive function and the content of BDNF in hippocampus of rats with chronic cerebral ischemia by using water maze, Western blot and Golgi staining.
Materials and methods
SD rats (healthy male) 240, about 24 weeks old, weight about 450g, were provided by the experimental animal supply center of Zhengzhou University medical college. They were randomly divided into sham operation group, model group and experimental group, and 20 rats in each group were given a time point on Thursday after the drug administration. The experimental group was given 30mg/kg / dESC gavage every day for the 2VO model rats, and the bilateral common carotid artery was permanent. The chronic cerebral ischemia model was established by blocking method (2VO). The drug was selected for the time point of 1,2,4,8 on Thursday. The cognitive function of rats in each group was detected by the Morris water maze. The expression of BDNF in the hippocampus of the rats was detected by Western blot. The length of the dendrites, the branches and the density of the dendritic spines were observed by Golgi staining.
Result
1. Effect of ESC on cognitive function in rats with chronic cerebral ischemia
There was no significant difference in the escape latency between the rats in the sham operation group (P0.05): the escape latency of the rats in the experimental group was significantly shorter than that in the control group (P0.05), and the escape latency of the experimental group and the model group was significantly longer than that of the sham group (P0.05).
2. Effect of ESC on BDNF Expression in Hippocampus of Rats with Chronic Cerebral Ischemia
At the same observation point, the levels of BDNF in hippocampus of experimental group and model group were lower than those of sham operation group (P 0.05), and the levels of BDNF in hippocampus of experimental group were higher than those of model group (P 0.05).
3. Effect of ESC on morphology of macropyramidal cells in hippocampus of rats with chronic cerebral ischemia
In the model group and the experimental group, the dendrite length, the branch and the density of the dendritic spines in the hippocampal CA1 region were significantly lower than those in the sham operation group (P0.05). The dendritic branches and length of the large pyramidal cells in the hippocampus CA1 region and the density of the dendritic spines increased significantly (P0.05).
conclusion
Ai Sciplan can significantly delay the progress of cognitive impairment in rats with chronic cerebral ischemia. The mechanism may be to improve the learning and memory ability by promoting the expression of BDNF.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R743

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