【摘要】：目的：在我國(guó)，血管性認(rèn)知障礙（vascular cognitive impairment,VCI）是老年期癡呆的主要組成部分，不僅會(huì)嚴(yán)重?fù)p害患者的健康及生存質(zhì)量，也給社會(huì)和家庭帶來(lái)了沉重負(fù)擔(dān)。目前，VCI的發(fā)病機(jī)制尚不十分清楚，也無(wú)特殊有效的治療方法，因此探討VCI的發(fā)病機(jī)理，制定合理的治療方案，是醫(yī)學(xué)領(lǐng)域研究中的重要課題。慢性腦低灌注是VCI、阿爾茨海默病(Alzheimer's Disease,AD)等多種神經(jīng)系統(tǒng)疾病發(fā)生發(fā)展過程中的一個(gè)共同病理過程。慢性腦供血不足發(fā)病早期以輕度認(rèn)知障礙為主要表現(xiàn)，最終可導(dǎo)致持久或進(jìn)展性的認(rèn)知與神經(jīng)功能障礙。有研究指出，犬尿氨酸通路相關(guān)代謝產(chǎn)物可以引起神經(jīng)系統(tǒng)損害，可能是產(chǎn)生腦實(shí)質(zhì)和腦微血管系統(tǒng)損害的重要物質(zhì)，故我將通過檢測(cè)吲哚胺-2,3-雙加氧酶(indoleamine2,3-dioxygenase,IDO)、犬尿氨酸(kynurenine,Kyn)等相關(guān)因子，探討犬尿氨酸通路相關(guān)代謝產(chǎn)物在慢性腦低灌注所致認(rèn)知障礙的作用。 方法：用健康雄性Wistar大鼠30只，鼠齡3~4個(gè)月，體質(zhì)量200～250g，隨機(jī)分成實(shí)驗(yàn)組（n=15），假手術(shù)對(duì)照組（n=15）。實(shí)驗(yàn)組大鼠行改良的雙側(cè)頸總動(dòng)脈結(jié)扎術(shù),假手術(shù)組大鼠除不結(jié)扎雙側(cè)頸總動(dòng)脈外,余處理同實(shí)驗(yàn)組。各組大鼠術(shù)后4周在水迷宮測(cè)試后斷頭，在冰上快速取海馬組織。行免疫組化染色觀察海馬病理變化和海馬IFN-γ、TNF-a、iNOS表達(dá)變化。行ELISA法顯示IDO、KYN含量變化。運(yùn)用SPSS17.0統(tǒng)計(jì)軟件進(jìn)行比較，，P0.05表示有統(tǒng)計(jì)學(xué)意義。 結(jié)果：（1）兩組大鼠存活情況：實(shí)驗(yàn)組大鼠死亡2只，死亡率為13.3%；假手術(shù)組大鼠全部存活。（2）水迷宮試驗(yàn)：實(shí)驗(yàn)組大鼠學(xué)習(xí)、記憶成績(jī)顯著下降，表現(xiàn)為逃避潛伏期延長(zhǎng)，平臺(tái)象限游泳距離百分比減少，明顯高于假手術(shù)組（P0.05）。(3)免疫組織化學(xué)方法顯示海馬CA1區(qū)IFN-γ、TNF-a、iNOS表達(dá)變化：假手術(shù)組海馬CA1區(qū)僅見極少量陽(yáng)性神經(jīng)元；實(shí)驗(yàn)組可見大量陽(yáng)性神經(jīng)元，且排列松散，胞體變小，核固縮，陽(yáng)性細(xì)胞累計(jì)光密度（IOD）值高于假手術(shù)組(P0.05)。（4）ELISA法提示，實(shí)驗(yàn)組大鼠海馬IDO及KYN濃度多于對(duì)照組(P0.05)。 結(jié)論：(1)通過水迷宮證實(shí)了慢性腦低灌注大鼠存在學(xué)習(xí)和記憶功能障礙。(2)采用免疫組織化學(xué)方法，證實(shí)了在慢性腦低灌注狀態(tài)下大鼠海馬組織IFN-γ、TNF-a表達(dá)增加，說明慢性腦低灌注大鼠的病理生理過程包含著炎性反應(yīng)，而炎性反應(yīng)的發(fā)生很可能刺激了IDO的高表達(dá)。(3)實(shí)驗(yàn)組海馬IDO、KYN含量顯著增加，提示在慢性腦低灌注中伴隨著KYN、IDO的蓄積，從而有可能引起腦損傷，參與慢性腦低灌注致認(rèn)知障礙的過程。
[Abstract]:Objective: vascular cognitive impairment (vascular cognitive) is a major component of senile dementia in China, which not only seriously damages the health and quality of life of patients, but also brings a heavy burden to society and family. At present, the pathogenesis of VCI is not very clear, and there is no special and effective treatment method. Therefore, it is an important subject in the field of medicine to explore the pathogenesis of VCI and formulate a reasonable treatment scheme. Chronic cerebral hypoperfusion is a common pathological process in the occurrence and development of many nervous system diseases such as VCI, Alzheimer's disease (AD) and so on. Mild cognitive impairment is the main manifestation in the early stage of chronic cerebral blood supply insufficiency, which can eventually lead to persistent or progressive cognitive and neurological dysfunction. Studies have shown that the metabolites associated with the canine uric acid pathway can cause damage to the nervous system and may be important substances that cause damage to the brain parenchyma and the brain microvascular system. Therefore, we will investigate the role of the metabolites of canine uremic acid pathway in cognitive impairment induced by chronic cerebral hypoperfusion by detecting indoleamine-3-dioxygenase (IDO) and kynurenine (kynurenine kyn) and other related factors. Methods: 30 healthy male Wistar rats, aged 3 ~ 4 months, were randomly divided into experimental group (n = 15) and sham operation control group (n = 15). Rats in the experimental group were treated with modified bilateral common carotid artery ligation, and the sham-operated rats were treated the same as the experimental group except the bilateral common carotid artery was not ligated. Four weeks after operation, the rats were severed after water maze test, and hippocampal tissue was quickly removed from the ice. The pathological changes of hippocampus and the expression of IFN- 緯 -TNF-aF- iNOS in hippocampus were observed by immunohistochemical staining. ELISA method was used to show the change of IDOKYN content. The use of SPSS17.0 statistical software to compare P05 indicated that there was statistical significance. Results: (1) the survival of rats in the two groups: two rats died in the experimental group, the mortality was 13.3%, and all the rats in the sham operation group survived. (2) the water maze test showed that the rats in the experimental group were learning, the memory scores were significantly decreased, and the escape latency was prolonged. The percentage of swimming distance in platform quadrant decreased, which was significantly higher than that in sham-operated group (P0.05). (3). The expression of IFN- 緯 -TNF-afi-iNOS in hippocampal CA1 area was significantly higher than that in sham-operated group (P0.05). (3). Only a few positive neurons were found in CA1 area of hippocampus in sham operation group, and a large number of positive neurons were found in experimental group. The (IOD) value of the positive cells was higher than that of the sham-operated group (P0.05). (4) ELISA method. The concentration of IDO and KYN in the hippocampus of the experimental group was higher than that of the control group (P0.05). Conclusion: (1) Learning and memory dysfunction in rats with chronic cerebral hypoperfusion was confirmed by water maze. (2) the expression of IFN- 緯 -TNF-a in hippocampus of chronic cerebral hypoperfusion rats was confirmed by immunohistochemical method. It was suggested that the pathophysiological process of chronic cerebral hypoperfusion rats included inflammatory response, and the occurrence of inflammatory reaction probably stimulated the high expression of IDO. (3) the content of IDOKYN in hippocampus of experimental group increased significantly, which suggested that the accumulation of KYN IDO was associated with chronic cerebral hypoperfusion. This may lead to brain injury and participate in the process of cognitive impairment caused by chronic cerebral hypoperfusion.
【學(xué)位授予單位】：山西醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2013
【分類號(hào)】：R749.16

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