本文選題：蛛網(wǎng)膜下腔出血 + 早期腦損傷　； 參考：《浙江大學(xué)》2016年博士論文

【摘要】：研究背景自發(fā)性蛛網(wǎng)膜下腔出血(spontaneous subarachnoid hemorrhage, SAH)是神經(jīng)外科常見(jiàn)的危重急癥,大約30%的病人在發(fā)病初期死亡,10%的病人死于其后續(xù)發(fā)生的各種并發(fā)癥,其總體死亡率高達(dá)50%。自發(fā)性蛛網(wǎng)膜下腔出血大約占所有中風(fēng)疾病的5-7%,全世界的發(fā)病率大約為10/10萬(wàn)人。大多數(shù)患者死亡發(fā)生于疾病早期,其中最主要原因是自發(fā)性蛛網(wǎng)膜下腔出血或者并發(fā)急性腦積水后導(dǎo)致的顱內(nèi)壓急劇增高。進(jìn)一步的基礎(chǔ)研究表明自發(fā)性蛛網(wǎng)膜下腔出血后早期腦損傷(Early brain injury, EBI)是導(dǎo)致高死亡率和致殘率的主要原因。早期腦損傷是指從蛛網(wǎng)膜下腔出血開(kāi)始至72小時(shí)這一時(shí)間窗之內(nèi)的腦損傷,它是一個(gè)非常復(fù)雜的病理生理學(xué)過(guò)程。目前的研究認(rèn)為早期腦損傷主要與顱內(nèi)壓升高、腦血流量降低、腦灌注壓下降、血腦屏障破壞和腦水腫等有關(guān),同時(shí)還有很多研究證據(jù)表明凋亡是早期腦損傷的主要病理改變因,神經(jīng)元與內(nèi)皮細(xì)胞的凋亡在蛛網(wǎng)膜下腔出血模型中均有報(bào)道,而且均與腦水腫密切相關(guān)。腫瘤抑制因子p53是非常重要的凋亡調(diào)控因子,蛛網(wǎng)膜下腔出血后發(fā)現(xiàn)p53的表達(dá)水平明顯增高。而p53又是最早被發(fā)現(xiàn)能被乙酰化調(diào)節(jié)而且非組蛋白的蛋白質(zhì),當(dāng)p53末端的賴氨酸被乙�；�,將激活p53增強(qiáng)其對(duì)下游分子的轉(zhuǎn)錄,比如Bax, Puma, Noxa, Bid等凋亡促進(jìn)分子從而起到促進(jìn)凋亡的作用。關(guān)于p53乙�；M(jìn)一步研究發(fā)現(xiàn),乙�；饔媚茉谕毁嚢彼嵛稽c(diǎn)與其他蛋白修飾作用競(jìng)爭(zhēng)比如泛素化和甲基化,從而調(diào)節(jié)其轉(zhuǎn)錄的活性甚并起到進(jìn)一步調(diào)節(jié)生物功能的目的。以往的實(shí)驗(yàn)證據(jù)表明蛋白的乙�；蕾囉谌ヒ阴；讣易宸肿拥淖饔�,p53的去乙�；{(diào)控就是依賴于去乙�；傅淖饔�。Sirtuins家族屬于Ⅲ類去乙�；讣易�,它能夠?qū)M蛋白或非組蛋白去乙�；�。SIRT1是哺乳動(dòng)物sirtuins家族成員中研究最多,在以往的研究中發(fā)現(xiàn)其在多種生理或者病理過(guò)程中起到重要的調(diào)控作用。除了能夠?qū)1、H3和H4去乙�；�,它還被發(fā)現(xiàn)能對(duì)p53、NF-κB、FoxO等轉(zhuǎn)錄因子去乙�；�,因此在理論上SIRT1能夠通過(guò)對(duì)上述蛋白乙�；癄顟B(tài)的調(diào)節(jié)而具有調(diào)節(jié)細(xì)胞周期,凋亡和腫瘤抑制的作用。很多體外或者體內(nèi)研究證實(shí)SIRT1能夠通過(guò)對(duì)重要分子去乙�；恼{(diào)節(jié)而對(duì)心腦等器官起到很好的保護(hù)作用。白藜蘆醇是一種天然存在化合物,在多種植物中含量很高比如葡萄皮中,同時(shí)它也是SIRT1的一種激活劑,在許多研究中它被發(fā)現(xiàn)能夠具有類似于熱量限制(calorie restriction, CR)帶來(lái)的生物體生命周期延長(zhǎng)的作用。相反sirtinol是SIRT1的抑制劑,在多個(gè)研究中通過(guò)抑制SIRT1的活性來(lái)驗(yàn)證SIRT1在不同生物或生理活動(dòng)中的作用。本研究將觀察SIRT1在蛛網(wǎng)膜下腔出血早期腦損傷中后其表達(dá)調(diào)控情況以及其對(duì)神經(jīng)元凋亡、腦水腫和神經(jīng)功能的影響,然后通過(guò)激活與抑制SIRT1來(lái)進(jìn)一步闡明SIRT1在蛛網(wǎng)膜下腔出血后早期腦損傷中的作用機(jī)制。實(shí)驗(yàn)方法第一部分首先采用頸內(nèi)動(dòng)脈線栓穿刺法制作大鼠蛛網(wǎng)膜下腔出血模型。成年雄性SD大鼠被隨機(jī)分為：假手術(shù)組(Sham組),蛛網(wǎng)膜下腔出血組(SAH組),SAH組按取材時(shí)間不同又分為蛛網(wǎng)膜下腔出血后6h組(SAH 6h組),蛛網(wǎng)膜下腔出血后24h組(SAH 24h組),蛛網(wǎng)膜下腔出血48h組(SAH48h組)。通過(guò)神經(jīng)功能缺陷評(píng)分,腦水含量測(cè)定檢測(cè)腦損傷程度。采用Western blot檢測(cè)自SIRT1的表達(dá)和凋亡相關(guān)蛋白(p53及其乙�；癄顟B(tài))的表達(dá)；采用免疫熒光法檢測(cè)神經(jīng)元凋亡細(xì)胞數(shù)目。第二部分1.成年雄性SD大鼠被隨機(jī)分為：假手術(shù)+溶劑組(Sham組)、蛛網(wǎng)膜下腔出血+溶劑組(SAH組)和蛛網(wǎng)膜下腔出血+白藜蘆醇預(yù)處理組(SAH+RES組)(模型制作前48小時(shí)開(kāi)始每日腹腔注射白藜蘆醇(100mg/kg))。通過(guò)神經(jīng)功能缺陷評(píng)分,不同部位腦組織的腦水含量測(cè)定檢測(cè)早期腦損傷程度。2.成年雄性SD大鼠被隨機(jī)分為：假手術(shù)組(Sham組),蛛網(wǎng)膜下腔出血組(SAH組),蛛網(wǎng)膜下腔出血+溶劑組(SAH+SOL),蛛網(wǎng)膜下腔出血+白藜蘆醇組(SAH+RES),蛛網(wǎng)膜下腔出血+白藜蘆醇+腦室DMSO組(SAH+RES+DMSO)和蛛網(wǎng)膜下腔出血+白藜蘆醇+腦室sirtinol組(SAH+RES+SIR).白藜蘆醇在蛛網(wǎng)膜下腔出血模型制作前48小時(shí)腹腔注射100mg/kg, sirtinol為腦室注射10ul, Sham組除不刺穿頸內(nèi)動(dòng)脈外其余操作與SAH組相同,(SAH+RES+DMSO)組腦室內(nèi)注射與sirtinol等體積DMSO.然后在蛛網(wǎng)膜下腔出血模型制作完成后24小時(shí)采集數(shù)據(jù)：神經(jīng)功能功能缺陷評(píng)分,不同部位腦組織的腦水含量測(cè)定,Evans blue評(píng)估血腦屏障破壞程度；采用Western blot法檢測(cè)ZO-1、Occludin、cluadin5、SIRT1、凋亡相關(guān)蛋白p53及其乙�；癄顟B(tài)和凋亡相關(guān)蛋白(活化的caspase3)的表達(dá)；免疫熒光多重標(biāo)記法檢測(cè)神經(jīng)元細(xì)胞凋亡情況；實(shí)時(shí)熒光定量PCR檢測(cè)p53下游調(diào)控蛋白(Bax, Puma, Noxa, Bid)的mRNA表達(dá)情況。結(jié)果第一部分蛛網(wǎng)膜下腔出血后48h內(nèi)大鼠的腦水含量上升程度和神經(jīng)功能評(píng)分下降程度在24h時(shí)達(dá)到最大值,western blot結(jié)果顯示蛛網(wǎng)膜下腔出血后SIRT1在24小時(shí)達(dá)到低谷,此時(shí)p53表達(dá)達(dá)高峰,其乙�；竭_(dá)高峰。免疫組織化學(xué)結(jié)果提示,蛛網(wǎng)膜下腔出血后24h,腦組織TUNEL陽(yáng)性標(biāo)記的凋亡細(xì)胞數(shù)增力口,TUNEL和神經(jīng)元標(biāo)記物NeuN共熒光定位,提示凋亡在神經(jīng)元細(xì)胞發(fā)生。第二部分1.蛛網(wǎng)膜下腔出血24小時(shí)后通過(guò)腦水含量及神經(jīng)功能的評(píng)估發(fā)現(xiàn)白藜蘆醇預(yù)處理緩解了左右腦半球腦水含量的上升和神經(jīng)功能缺陷,白藜蘆醇預(yù)處理降低了蛛網(wǎng)膜下腔出血后大鼠的死亡率。2.蛛網(wǎng)膜下腔出血24小時(shí)后觀察發(fā)現(xiàn)白藜蘆醇預(yù)處理緩解了左右腦半球腦水含量的上升和神經(jīng)功能缺陷,而sirtinol逆轉(zhuǎn)了白藜蘆醇的作用。通過(guò)測(cè)量腦組織Evans Blue的含量發(fā)現(xiàn),蛛網(wǎng)膜下腔出血后血腦屏障嚴(yán)重破壞,白藜蘆醇預(yù)處理保護(hù)了血腦屏障(減少Evans blue滲出),而sirtinol作用以后原本減少的Evans blue又增多了,說(shuō)明其逆轉(zhuǎn)了白藜蘆醇的血腦屏障保護(hù)作用。通過(guò)western blot檢測(cè)發(fā)現(xiàn),蛛網(wǎng)膜下腔出血后24小時(shí)ZO-1、Occludin. Claudin5等緊密鏈接蛋白表達(dá)下降是導(dǎo)致血腦屏障通透性增加的直接原因之一,白藜蘆醇預(yù)處理能上調(diào)其表達(dá)水平從而減輕血腦屏障通透性的增加,但使用了sirtinol之后白藜蘆醇上調(diào)上述緊密連接蛋白的作用被逆轉(zhuǎn)。在SIRT1激活方面的作用,白藜蘆醇預(yù)處理使蛛網(wǎng)膜下腔出血后SIRT1表達(dá)下降得到減輕,而sirtinol能夠反轉(zhuǎn)白藜蘆醇對(duì)SIRT1表達(dá)上調(diào)的作用；同時(shí)白藜蘆醇能夠明顯減少p53和乙酰化p53的水平,降低了激活的caspase3的表達(dá),而Sirtinol則逆轉(zhuǎn)了白藜蘆醇下調(diào)p53、乙酰化p53和激活的caspase3的作用。進(jìn)一步通過(guò)TUNEL和NeuN免疫熒光共定位方法檢測(cè)凋亡神經(jīng)元數(shù)目發(fā)現(xiàn),白藜蘆醇預(yù)處理可以明顯減少凋亡神經(jīng)元數(shù)目,sirtinol抑制了白藜蘆醇的減輕神經(jīng)元凋亡的作用。通過(guò)熒光定量PCR檢測(cè)發(fā)現(xiàn)白藜蘆醇預(yù)處理明顯減少了BaxmRNA水平,其余幾個(gè)凋亡相關(guān)蛋白的mRNA水平有下降的趨勢(shì)但未發(fā)現(xiàn)統(tǒng)計(jì)學(xué)差異；而sirtinol明顯抑制了白藜蘆醇對(duì)Bax mRNA水平下調(diào)的作用。結(jié)論第一部分大鼠頸內(nèi)動(dòng)脈穿刺的蛛網(wǎng)膜下腔出血觀察返現(xiàn)腦水腫、p53和乙�；痯53均在24小時(shí)達(dá)到高峰,神經(jīng)功能缺陷明顯,而SIRT1在此時(shí)最低,結(jié)合神經(jīng)元凋亡情況,提示SIRT1可能參與了蛛網(wǎng)膜下腔出血早期腦損傷相關(guān)的后神經(jīng)元凋亡的調(diào)控。第二部分白藜蘆醇預(yù)處理能夠改善蛛網(wǎng)膜下腔出血后大鼠神經(jīng)功能缺陷,減輕腦水腫；通過(guò)白藜蘆醇預(yù)處理和sirtinol逆轉(zhuǎn)白藜蘆醇的研究發(fā)現(xiàn)：白藜蘆醇其血腦屏障保護(hù)可能是通過(guò)上調(diào)ZO-1、Occludin、Claudin5等緊密連接蛋白而起作用,同時(shí)白藜蘆醇上調(diào)了SIRT1的表達(dá)水平,降低了p53和乙�；痯53的水平,激活的caspase3也下降了,免疫熒光檢查也證實(shí)白藜蘆醇預(yù)處理使凋亡的神經(jīng)元細(xì)胞減少；相反使用SIRT1抑制劑sirtinol在各方面抑制了白藜蘆醇的神經(jīng)元保護(hù)作用,腦水腫減輕被逆轉(zhuǎn)、減少的Evans blue滲出又開(kāi)始增多、被白藜蘆醇減輕的大鼠神經(jīng)功能缺陷再次加重,分子檢測(cè)方面ZO-1、Occludin、Claudin5等血腦屏障相關(guān)蛋白再次下調(diào),SIRT1表達(dá)水平低于單獨(dú)白藜蘆醇預(yù)處理、p53和乙�；痯53水平轉(zhuǎn)向增高,凋亡神經(jīng)元數(shù)目增高。通過(guò)使用SIRT1增強(qiáng)劑和抑制劑從神經(jīng)功能、腦水腫和血腦屏障檢測(cè),進(jìn)而在信號(hào)通路等分子水平說(shuō)明SIRT1信號(hào)通路在蛛網(wǎng)膜下腔出血后起到重要調(diào)節(jié)作用,進(jìn)而減輕腦水腫、保護(hù)血腦屏障、減少神經(jīng)元凋亡、改善神經(jīng)功能。
[Abstract]:Spontaneous subarachnoid hemorrhage (SAH) is a common critical emergency in the Department of neurosurgery. About 30% of the patients died at the beginning of the onset, and 10% of the patients died of subsequent complications. The overall mortality rate was as high as 50%. spontaneous subarachnoid hemorrhage accounted for all apoplexy diseases. The incidence of 5-7% in the world is about 10/10 million. Most of the patients died in the early stages of the disease, the main cause of which was the spontaneous subarachnoid hemorrhage or the rapid increase of intracranial pressure following acute hydrocephalus. Further basic studies showed early brain injury (Early brain) after spontaneous subarachnoid hemorrhage. Injury, EBI) is the main cause of high mortality and disability. Early brain injury is a very complicated pathophysiological process from the beginning of subarachnoid hemorrhage to 72 hours. It is a very complicated pathophysiological process. The decline, blood brain barrier destruction and brain edema are related, and there are many research evidence that apoptosis is the main cause of early brain damage. Apoptosis of neurons and endothelial cells is reported in the subarachnoid hemorrhage model, and it is closely related to brain edema. Tumor suppressor factor p53 is a very important regulation of apoptosis. After subarachnoid hemorrhage, the expression level of p53 was significantly increased. And p53 was the earliest protein that was found to be acetylation and non histone. When lysine at the p53 terminal was acetylated, it activated p53 to enhance the transcription of its downstream molecules, such as Bax, Puma, Noxa, Bid and so on to promote apoptosis. Further studies on p53 acetylation have found that acetylation can compete with other proteins at the same lysine site to compete with other proteins such as ubiquitination and methylation, thus regulating its transcriptional activity and further regulating biological functions. Previous experimental evidence showed that acetylation of protein was dependent on deacetylation. The role of enzyme family molecules, p53 deacetylation regulation is dependent on the action of deacetylase, the.Sirtuins family belongs to class III deacetylase family. It can study histone or non histone.SIRT1 in mammalian sirtuins family members most. In the study, it is found in a variety of Physiology or pathology. In addition to the ability to deacetylation of H1, H3 and H4, it is also found to be able to deacetylation of p53, NF- kappa B, FoxO and other transcription factors, so in theory SIRT1 can regulate cell cycle, apoptosis and tumor inhibition by regulating the state of acetylation of these proteins. Many in vitro or in vivo SIRT1 Internal research has confirmed that SIRT1 can protect the heart and brain by regulating the deacetylation of important molecules. Resveratrol is a natural compound, which is very high in a variety of plants, such as grape skin, and is also an activator of SIRT1. In many studies it has been found to be similar to that. The effect of the life cycle prolongation of calorie restriction (CR). Reverse sirtinol is an inhibitor of SIRT1. In several studies, the role of SIRT1 in different biological or physiological activities is verified by inhibiting the activity of SIRT1. This study will observe the expression of SIRT1 in the early brain damage of subarachnoid hemorrhage. The effect of control and its effect on neuronal apoptosis, brain edema and nerve function, and then further elucidate the mechanism of the action of SIRT1 in early brain injury after subarachnoid hemorrhage by activating and inhibiting SIRT1. SD rats were randomly divided into sham operation group (group Sham), subarachnoid hemorrhage group (group SAH), group SAH was divided into group 6h (group SAH 6h) after subarachnoid hemorrhage, 24h group (SAH 24h group) after subarachnoid hemorrhage, 48h group of subarachnoid hemorrhage (SAH48h group) after subarachnoid hemorrhage, and the determination of brain water content by nerve function defect score. The expression of self SIRT1 and the expression of apoptosis related protein (p53 and its acetylation state) were detected by Western blot, and the number of apoptotic cells was detected by immunofluorescence. Second part 1. adult male SD rats were randomly divided into sham operation + solvent group (Sham group), subarachnoid hemorrhage + solvent group (SAH group) and spiders Subomentum hemorrhage + resveratrol preconditioning group (group SAH+RES) (group SAH+RES, 100mg/kg) was injected daily 48 hours before the model was made. Through the neurological deficit score, the brain water content in different parts of the brain was measured and the adult male SD rats were randomly divided into the sham operation group (group Sham) and the arachnoid arachnoid Lower hemorrhage group (group SAH), subarachnoid hemorrhage + solvent group (SAH+SOL), subarachnoid hemorrhage + resveratrol group (SAH+RES), subarachnoid hemorrhage + resveratrol + ventricle DMSO group (SAH+RES+DMSO) and subarachnoid hemorrhage + resveratrol + ventricle sirtinol group (SAH+RES+SIR). Resveratrol was 48 small before the subarachnoid hemorrhage model Intraperitoneal injection of 100mg/kg, sirtinol for intraventricular injection of 10ul, group Sham in addition to the internal carotid artery, the rest of the operation is the same as the SAH group, (SAH+RES+DMSO) group intracerebral injection and sirtinol volume DMSO. and then the subarachnoid hemorrhage model was completed 24 hours after the completion of the data: neural function defect score, different parts of the brain tissue Determination of brain water content and Evans blue to evaluate the damage of blood brain barrier; Western blot method was used to detect the expression of ZO-1, Occludin, cluadin5, SIRT1, apoptosis related protein p53 and its state of acetylation and apoptosis related protein (activated Caspase3); immunofluorescence multiple labeling method was used to detect neuronal apoptosis; real-time fluorescent quantitative PCR The expression of mRNA in p53 downstream regulatory proteins (Bax, Puma, Noxa, Bid) was detected. Results after subarachnoid hemorrhage, the level of brain water content and the decrease of neural function score in 48h rats reached the maximum at 24h, and Western blot showed that after subarachnoid hemorrhage, the p53 table was reached at 24 hours. At the peak of dada peak, its acetylation level reached the peak. The immunohistochemical results suggested that 24h, TUNEL positive apoptotic cells in the brain tissue increased the number of apoptotic cells after subarachnoid hemorrhage, TUNEL and neuron marker NeuN co fluorescence localization, suggesting that apoptosis occurred in the neuron cells. The second part of subarachnoid hemorrhage was contained in brain water after 24 hours of subarachnoid hemorrhage. Resveratrol pretreatment relieved the increase of brain water content and neural dysfunction in the left and right hemispheres. Resveratrol pretreatment reduced the mortality of rats after subarachnoid hemorrhage.2. after subarachnoid hemorrhage 24 hours after subarachnoid hemorrhage observed that resveratrol preconditioning relieved the brain water content in the left and right hemispheres Sirtinol reversed the effect of resveratrol on the rise and neural dysfunction. By measuring the content of Evans Blue in the brain tissue, the blood brain barrier was seriously damaged after subarachnoid hemorrhage, and resveratrol pretreated the blood brain barrier (reducing the Evans blue exudation), and the decreased Evans blue increased after the sirtinol action. It is shown that it reverses the protective effect of resveratrol on the blood brain barrier. Through Western blot detection, it is found that the decrease of the expression of close linked protein 24 hours after subarachnoid hemorrhage, ZO-1, Occludin. Claudin5, is one of the direct causes of the increase of blood brain barrier permeability, and resveratrol preconditioning can increase the expression level and reduce the blood brain. The barrier permeability increased, but the effect of resveratrol on up - regulation of the close connexin was reversed after the use of sirtinol. In the activation of SIRT1, resveratrol pretreated the decrease of SIRT1 expression after subarachnoid hemorrhage, while sirtinol could reverse the effect of resveratrol on the up regulation of SIRT1 expression; and resveratrol Resveratol significantly reduced the level of p53 and acetylation of p53 and reduced the expression of activated Caspase3, while Sirtinol reversed the effect of resveratrol on p53, acetylated p53 and activated Caspase3. The number of apoptotic neurons was detected by TUNEL and NeuN immunofluorescence method, and resveratrol pretreatment could be significantly reduced. The number of fewer apoptotic neurons, sirtinol inhibited the effect of resveratrol on the reduction of neuronal apoptosis. By fluorescence quantitative PCR detection, resveratrol pretreatment significantly reduced the level of BaxmRNA, and the mRNA level of the remaining apoptosis related proteins decreased but no statistical difference was found, while sirtinol significantly inhibited resveratrol. The effect of alcohol on the downregulation of Bax mRNA. Conclusion the first part of the subarachnoid hemorrhage of the internal carotid artery of the rat was observed to return to the brain edema. P53 and acetylated p53 reached the peak at 24 hours, and the nerve function defects were obvious, and SIRT1 was the lowest at this time, combining with the neuron apoptosis, suggesting that SIRT1 may be involved in the early subarachnoid hemorrhage. The second part of resveratrol pretreatment can improve the neural function defects and reduce the brain edema after subarachnoid hemorrhage. The study of resveratrol pretreatment and sirtinol reversal of resveratrol may be found that the protection of resveratrol on the blood brain barrier may be by up regulation of ZO-1, Occludin Claudin5 and other close connexin played a role, while resveratrol up-regulated the expression of SIRT1, reduced the level of p53 and acetylation of p53, and decreased the activation of Caspase3. Immunofluorescence also confirmed that resveratrol pretreated the apoptotic neuron cells, and SIRT1 inhibitor sirtinol was suppressed in all aspects. The neuroprotective effect of resveratrol was reversed, the decrease of brain edema was reversed, the decrease of Evans blue exudation began to increase, and the neural functional defects of rats reduced by resveratrol were aggravated again. The molecular detection of ZO-1, Occludin, Claudin5 and other blood brain barrier related proteins decreased again, and the expression level of SIRT1 was lower than that of resveratrol alone, p53 And the level of acetylated p53 increased and the number of apoptotic neurons increased. By using SIRT1 enhancers and inhibitors from neural function, brain edema and blood brain barrier detection, and then at the signal pathway, the SIRT1 signaling pathway was played an important role in the subarachnoid hemorrhage, thus alleviating brain edema and protecting the blood brain barrier, Reduce neuron apoptosis and improve nerve function.

【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R743.35

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