本文關(guān)鍵詞： 腦缺血再灌注損傷 氧化應(yīng)激 根皮素 超氧化物歧化酶 谷胱甘肽 谷胱甘肽過氧化物酶 丙二醛 Nrf2途徑　出處：《山東大學(xué)》2016年博士論文　論文類型：學(xué)位論文

【摘要】：缺血性腦血管病的高發(fā)病率、致殘率嚴(yán)重影響千萬患者的生命健康,但改善腦供血同時(shí)帶來的腦缺血再灌注損傷也成為缺血性腦血管病治療的難題之一。腦缺血再灌注損傷機(jī)制尚不明確,目前認(rèn)為有多種因素參與損傷過程,氧化應(yīng)激被認(rèn)為是腦缺血再灌注損傷的一個(gè)主要因素。由于各種原因造成組織細(xì)胞的氧化和抗氧化平衡破壞,致使自由基生成過多或者清除不足,因而造成機(jī)體損傷結(jié)構(gòu)和功能損傷,即氧化應(yīng)激。因此,針對氧化應(yīng)激的神經(jīng)保護(hù)策略可以顯著提高干預(yù)中風(fēng)的成效。近年發(fā)現(xiàn),幾乎所有具有保護(hù)作用的抗氧化基因均存在抗氧化反應(yīng)元件(ARE),包括氧化應(yīng)激在內(nèi)的各種因素可導(dǎo)致Nrf2易位細(xì)胞核內(nèi)作用于ARE,激活抗氧化基因的表達(dá),由此保護(hù)組織細(xì)胞免受氧化應(yīng)激損傷,因此激活Nrf2途徑,從而啟動(dòng)機(jī)體抗氧化應(yīng)激反應(yīng)成為改善氧化應(yīng)激造成的腦缺血再灌注損傷的可行方向。Nrf2/ARE通路已經(jīng)被證明是抗氧化應(yīng)激最重要的一條通路,這條通路的激活及上調(diào)在腦缺血再灌注損傷中可以起到抗氧化應(yīng)激及神經(jīng)保護(hù)作用。氧化應(yīng)激的發(fā)生可以激活Nrf2的表達(dá),而某些藥物可以通過上調(diào)Nrf2表達(dá)使機(jī)體增加抗氧化能力、減輕氧化損傷。但自由基本身十分活躍,加上檢測自由基的方法復(fù)雜難行,實(shí)踐中常以氧化應(yīng)激指示酶水平的變化情況來反映氧化應(yīng)激水平及損傷程度,故本實(shí)驗(yàn)選取SOD、GSH、GSH-PX、MDA作為指示機(jī)體氧化損傷程度及抗氧化應(yīng)激能力的指示酶。根皮素屬于二氫查耳酮的類黃酮家族,尤其在蘋果和蘋果的衍生產(chǎn)品中含量豐富,來源廣泛。大量的證據(jù)表明,根皮素具有抗氧化及神經(jīng)保護(hù)作用,在其他學(xué)者的多項(xiàng)實(shí)驗(yàn)中證實(shí)能夠通過調(diào)控Nrf2抗氧化應(yīng)激對組織功能起到保護(hù)作用,具有干預(yù)氧化應(yīng)激損傷腦缺血再灌注損傷的潛在影響。因此,我們進(jìn)行了本項(xiàng)實(shí)驗(yàn),研究腦缺血再灌注損傷過程中的腦損傷、氧化應(yīng)激指示酶變化與Nrf2表達(dá)的關(guān)系,以及經(jīng)過根皮素干預(yù)后上述指標(biāo)的變化對比,旨在揭示根皮素可以通過上調(diào)Nrf2表達(dá)對氧化應(yīng)激引起的腦缺血再灌注損傷起到保護(hù)作用。目的探討根皮素通過激活Nrf2途徑對腦缺血再灌注由氧化應(yīng)激導(dǎo)致的損傷的保護(hù)作用及相關(guān)機(jī)制,從而為腦缺血再灌注損傷提供新的干預(yù)方向。方法1.以體重在220-280mg的均齡清潔級SD健康人鼠為研究對象,所有動(dòng)物術(shù)前12 h禁食,所有的實(shí)驗(yàn)程序都按照國立實(shí)驗(yàn)室動(dòng)物的護(hù)理和使用健康指南進(jìn)行。該方案經(jīng)山東大學(xué)動(dòng)物倫理委員會批準(zhǔn)。將研究對象分為5組,分別為假手術(shù)組、I/R組(MCAO手術(shù)組)、根皮素干預(yù)組,根皮素干預(yù)組又分為三個(gè)亞組,分別為低劑量組、中劑量組、高劑量組。術(shù)前各根皮素組大鼠分別給予低劑量(20mg·Kg·D-1)、中劑量(40mg·Kg·D-1)、高劑量(80mg·Kg·D-1)艮皮素灌胃14天。末次給藥后1小時(shí)開始造模,其余各組給予等量生理鹽水灌胃。2.實(shí)驗(yàn)對象給予以10%水合氯醛35 mg/Kg腹腔注射麻醉,I/R組及根皮素組大鼠以改良后的線栓法阻斷右側(cè)大腦中動(dòng)脈(MCA),建立局限性腦缺血再灌注模型,模型成功的判斷標(biāo)準(zhǔn)：大鼠麻醉清醒后出現(xiàn)站立不穩(wěn),傾倒,左側(cè)肢體癱瘓,左爪不能伸展,醒后追尾,向右側(cè)行走,提尾時(shí)向一側(cè)轉(zhuǎn)圈。閉塞2小時(shí)后,拔出栓線實(shí)現(xiàn)血液再灌注,再灌注后24小時(shí)進(jìn)行后續(xù)實(shí)驗(yàn)。假手術(shù)組大鼠線栓插入深度8-10mm避免閉塞大腦中動(dòng)脈,其余操作與其他手術(shù)組相同。整個(gè)手術(shù)直腸溫度維持在37-38℃,房間溫度控制在25-27℃的范圍內(nèi)。3.再灌注24小時(shí)后,根據(jù)龍格等的5分制盲法對大鼠進(jìn)行神經(jīng)功能缺損評分：無明顯神經(jīng)損傷表現(xiàn)評0分；不能完全伸展對側(cè)前爪評1分；向?qū)?cè)轉(zhuǎn)圈評評2分；向?qū)?cè)傾倒評3分；不能自發(fā)行走,意識喪失評4分。得分越高,神經(jīng)功能損害越嚴(yán)重。神經(jīng)功能缺損評分后處死大鼠,分離腦組織,以2,3,5-三苯基四氮唑(TTC)染色,圖像用圖像分析軟件進(jìn)行分析,計(jì)算腦梗塞面積,對腦梗塞的程度進(jìn)行評估。4.處死大鼠后,用濕一干法測定腦水腫程度,摘除大腦兩個(gè)半球稱重(濕重),然后將組織在100℃下干燥24小時(shí),測定干重。公式計(jì)算：水含量=(濕重-干重)/濕重×重)測%。5.超氧化物歧化酶,谷胱甘肽、谷胱甘肽過氧化物酶可以反映機(jī)體抗氧化應(yīng)激水平,丙二醛可以間接反映氧化應(yīng)激導(dǎo)致的損傷,故選取超氧化物歧化酶,谷胱甘肽、谷胱甘肽過氧化物酶丙二醛為氧化應(yīng)激指示酶,以黃嘌呤氧化酶-羥胺法測定超氧化物歧化酶活性,微板法查谷胱甘肽及谷胱甘肽過氧化物酶活性,硫代巴比妥酸法測定丙二醛活性,蛋白質(zhì)濃度通過Bradford方法測定。6.采用RT-PCR和Western blot檢測大鼠Nrf2基因表達(dá)及蛋白水平。7.統(tǒng)計(jì)：應(yīng)用SPSS 13.0 (Statistical Package for the Social Sciences)統(tǒng)計(jì)軟件(SPSS,芝加哥,IL,USA)進(jìn)行統(tǒng)計(jì)分析,實(shí)驗(yàn)數(shù)據(jù)以均數(shù)士標(biāo)準(zhǔn)差(mean±SD)表示,采用單因素方差分析以及T檢驗(yàn),以P0.05視為差異有統(tǒng)計(jì)學(xué)意義。結(jié)果1.造模顯示,MCA閉塞2小時(shí)后再灌注24 h,假手術(shù)組大鼠反應(yīng)正常,肢體活動(dòng)無障礙,步態(tài)平穩(wěn),無神經(jīng)功能缺損癥狀；與假手術(shù)組相比,缺血／再灌注組大鼠出現(xiàn)站立不穩(wěn),左側(cè)肢體癱瘓,行走時(shí)向左側(cè)追尾,提尾時(shí)向左側(cè)側(cè)轉(zhuǎn)圈,提示局限性腦缺血再灌注損傷模型構(gòu)建成功。2.按照神經(jīng)功能缺損5分制評分,FR組大鼠神經(jīng)功能評分較假手術(shù)組明顯增高(P0.01),說明I/R組大鼠出現(xiàn)明顯神經(jīng)功能損害。根皮素干預(yù)各組大鼠神經(jīng)功能評分較假手術(shù)組大鼠增高,但較I/R組明顯降低(P0.05)。3.腦梗塞面積對比結(jié)果示,假手術(shù)組中為均勻紅色,沒有檢測到腦梗塞,而I/R組明顯可見廣泛白色梗塞病變,較假手術(shù)組梗塞面積明顯擴(kuò)大(PO.Q1)。根皮素各組梗塞面積與I/R組相比顯著減少,差異有統(tǒng)計(jì)學(xué)意義(P0.05)。4.腦水腫變化情況：假手術(shù)組腦含水量正常,I/R較假手術(shù)組腦水腫明顯(P0.01)。根皮素處理各組腦水腫程度較I/R組明顯下降(P0.05)。5.超氧化物歧化酶(SOD),谷胱甘肽(GSH)、谷胱甘肽過氧化物酶(GSH-PX).丙二醛(MDA)活力比較：灌注24小時(shí)后,與假手術(shù)組相比,I/R組超氧化物歧化酶,谷胱甘肽和谷胱甘肽過氧化物酶水平顯著降低(P0.01)。根皮素處理組超氧化物歧化酶,谷胱甘肽和谷胱甘肽過氧化物酶水平雖然較假手術(shù)組下降,但較I/R組明顯升高(P0.05)。I/R組丙二醛活力較假手術(shù)組明顯升高(P0.01)。根皮素干預(yù)組丙二醛水平較假手術(shù)組增高,但較相比I/R組顯著下降(P0.05)。6.RT-PCR及Western blot結(jié)果顯示,I／R組Nrf2的mRNA表達(dá)及蛋白水平較假手術(shù)組明顯升高(P0.05)。根皮素處理組Nrf2的mRNA表達(dá)及蛋白水平較I／R組顯著升高(P0.05)。結(jié)論1.腦缺血/再灌注可以造成明顯的腦神經(jīng)功能損傷和腦水腫、腦梗塞。2.腦缺血/再灌注導(dǎo)致超氧化物歧化酶,谷胱甘肽和谷胱甘肽過氧化物酶水平明顯下降,而丙二醛水平明顯升高,水平差異有統(tǒng)計(jì)學(xué)意義,表示缺血/再灌注導(dǎo)致腦組織抗氧化能力下降及明顯的氧化應(yīng)激損傷。3.各組根皮素干預(yù)后較1dR組大鼠腦神經(jīng)功能評分減少明顯,差異有統(tǒng)計(jì)學(xué)意義,說明根皮素能夠減輕腦缺血/再灌注導(dǎo)致神經(jīng)功能損害。4.根皮素組大鼠腦水腫及腦梗塞面積程度較I/R組明顯減輕,說明根皮素干預(yù)大鼠腦缺血/再灌注能夠明顯減輕腦水腫、腦梗塞。5.根皮素干預(yù)后超氧化物歧化酶,谷胱甘肽和谷胱甘肽過氧化物酶水平明顯較I/R組明顯升高,說明根皮素可以提高腦組織在缺血/再灌注時(shí)的抗氧化能力。6.根皮素干預(yù)后丙二醛水平較I/R組明顯下降,對比有統(tǒng)計(jì)學(xué)意義,說明根皮素能夠減輕腦缺血/再灌注的氧化應(yīng)激損傷。7.I/R組Nrf2的mRNA及蛋白表達(dá)較假手術(shù)組明顯增強(qiáng),差異有統(tǒng)計(jì)學(xué)意義,說明腦缺血/再灌注作為刺激源激活了Nrf2的基因表達(dá)。8.根皮素干預(yù)組的Nrf2的mRNA及蛋白表達(dá)較I/R組明顯增強(qiáng),差異有統(tǒng)計(jì)學(xué)意義,說明根皮素能夠上調(diào)Nrf2的基因表達(dá)。以上結(jié)果分析可以看出,腦缺血/再灌注過程存在明顯的氧化應(yīng)激損傷,而根皮素的干預(yù)可以明顯抑制腦缺血再灌注損傷過程中的氧化應(yīng)激反應(yīng),提高抗氧化水平,從而改善腦缺血再灌注損傷導(dǎo)致的腦組織損害以及腦功能評分。而Nrf2表達(dá)的上調(diào)與氧化應(yīng)激指示酶的變化及神經(jīng)功能評分下降、組織損害減輕同步,因此我們認(rèn)為,根皮素有可能通過上調(diào)Nrf2途徑起到抗氧化應(yīng)激作用從而在大鼠腦缺血／再灌注損傷中的抗氧化應(yīng)激從而對腦的起到神經(jīng)保護(hù)作用。
[Abstract]:Ischemic cerebrovascular disease with high incidence, disability rate must seriously affect the life and health of patients, but also bring about improving the blood supply to the brain of cerebral ischemia reperfusion injury has become one of the difficulties in the treatment of ischemic cerebrovascular disease. The mechanism of cerebral ischemia reperfusion injury is not clear, now that there are many factors involved in the process of oxidative stress injury. Is considered a major factor in cerebral ischemia reperfusion injury. Due to various reasons, the balance of oxidation and antioxidant causing tissue damage, resulting in the generation of free radicals, excessive or inadequate removal, which caused the injury can damage the structure and function, namely oxidative stress. Therefore, the neuroprotective strategies of oxidative stress can significantly improve the intervention of stroke results. In recent years, almost all have the protective effects of antioxidant genes have the antioxidant response element (ARE), including a variety of oxidative stress in the The role of factors can lead to translocation of Nrf2 nucleus in ARE, activate the expression of antioxidant genes, thereby protecting cells from oxidative stress injury, therefore the activation of the Nrf2 pathway, thereby initiating antioxidant stress become the improvement caused by oxidative stress in cerebral ischemia reperfusion injury in the feasible direction of.Nrf2/ARE pathway has been shown to be a pathway of oxidative stress importantly, activation and upregulation of this pathway in cerebral ischemia reperfusion injury can play a neuroprotective effect against oxidative stress and oxidative stress. The expression of Nrf2 can be activated, and some drugs can make the body to increase the antioxidant capacity by up regulating Nrf2 expression, reduce oxidative damage. But the free basic body is very active, and method for detection of free radicals is complicated and difficult, changes in practice often with oxidative stress indicator enzyme levels to reflect the level of oxidative stress and The extent of the damage, so this experiment selected SOD, GSH, GSH-PX, MDA as the indicator enzyme indicating the oxidative damage degree and antioxidant ability. The flavonoid family phloretin belongs to two dihydrochalcone, especially content in apple and the derivative products in rich, wide range of sources. A large amount of evidence that root bark pigment has antioxidant and neuroprotective effects, in a number of other scholars in the experiment proved to be regulated by Nrf2 oxidative stress to protect the organization function, with intervention on oxidative stress injury of cerebral ischemia reperfusion injury. The potential impact because of this, we carry out this experiment, brain injury of cerebral ischemia reperfusion injury in rats the relationship between oxidative stress, indicating enzymes and the expression of Nrf2, and after comparison of the change of root Pisugan prognosis of these indicators, in order to reveal phloretin can lead to oxidative stress by up regulating the expression of Nrf2 The cerebral ischemia reperfusion injury. Objective to investigate the protective effect of phloretin through activation of Nrf2 pathway on cerebral ischemia reperfusion injury caused by oxidative stress injury and the related mechanism, so as to provide the intervention of cerebral ischemia reperfusion injury. Methods 1. new directions to weight in 220-280mg were clean SD healthy people were as the research object, all animal preoperative fasting 12 h, all of the experimental procedures in accordance with the National Laboratory Animal Care and use of health guidelines. The plan is approved by the Shandong University animal ethics committee. The subjects were divided into 5 groups, namely sham operated group, I/R group (MCAO group), root Pisugan pretreatment group, root Pisugan pre group was divided into three subgroups, respectively, low dose group, middle dose group, high dose group. The preoperative phloretin group rats were given low dose (20mg - Kg - D-1), middle dose (40mg Kg D-1), high Dose (80mg Kg D-1) Gen meletin gavage for 14 days. 1 hours after the last administration began modeling, other groups were given normal saline.2. subjects given 10% chloral hydrate 35 mg/Kg intraperitoneal injection of anesthesia, I/R group and phloretin group rats were treated with modified thread occluding the right side of the brain artery (MCA), a limitation of the cerebral ischemia reperfusion model, criteria of success model: the rats were anesthetized awake after standing instability, dumping, left hemiparesis, left paw cannot extend, wake up to the right rear end, walking to the side. When the tail around the block 2 hours after the implementation of the blood reperfusion pull-out suture, 24 hours after reperfusion for subsequent experiments. The rats in the sham operation group the inserting depth of 8-10mm to avoid the middle cerebral artery occlusion, the same with other surgical group. The whole operation of rectal temperature at 37-38 degrees, the room temperature is controlled at 25-27 DEG C In the range of.3. after 24 hours of reperfusion, the neurological deficit scores of rats were divided into 5 blind method such as Runge system: no obvious neurological symptoms score of 0 points; can not fully extend the forepaw rated 1 points; to the contralateral circling judge 2 points; rated 3 points to the side of the dumping; not since the issuance, loss of consciousness, a score of 4 points. The higher the score, the more serious neurological damage. The neurological deficit score after the rats were sacrificed and brain tissues were isolated, with 2,3,5- three phenyl tetrazole (TTC) staining and image analysis using image analysis software, calculate the cerebral infarction area of cerebral infarction was performed to assess the degree of.4. the rats were sacrificed after the determination of the degree of brain edema by wet dry method, extraction of two hemispheres of the brain weight (wet weight), and then will be organized at 100 deg.c for 24 hours, the determination of dry weight. Formula: water content = (wet weight dry weight) / wet weight) *%.5. superoxide dismutase, glutathione Peptide, glutathione peroxidase can reflect the oxidative stress level of the body, MDA can indirectly reflect the damage caused by oxidative stress, so the selection of superoxide dismutase, glutathione, glutathione peroxidase as oxidative stress indicator enzyme, superoxide dismutase activity was determined by xanthine oxidase hydroxylamine method, micro plate method. Glutathione peroxidase activity determination of MDA and glutathione, thiobarbituric acid method, the protein concentration was determined by Bradford method using RT-PCR.6. and Western blot were detected Nrf2 gene expression and protein level of.7. statistics: application of SPSS 13 (Statistical Package for the Social Sciences) statistical software (SPSS, Chicago, IL, USA) for statistical analysis of experimental data. With the mean + standard deviation (mean + SD), using single factor analysis of variance and T test, with P0.05 as the difference Differences were statistically significant. Results 1. model showed that MCA occlusion 2 hours after reperfusion 24 h, rats in the sham operation group were normal reaction, disorder, no limb gait is smooth, no symptoms of neurological deficit; compared with sham operation group, ischemia / reperfusion group rats standing instability, left limb paralysis when walking to the left, rear end, tail to the left side when circling, reveals the limitation of cerebral ischemia reperfusion injury model was constructed successfully by.2. neural function defect score 5 points, FR group of rats neural function score was significantly higher than those in the sham operation group (P0.01), indicating significant neurological impairment in I rats in the /R group phloretin. Intervention rats neural function score compared with the sham operation group Shu Zenggao, but was lower than that of I/R group (P0.05).3. cerebral infarction area comparison showed that the sham group is uniform red, not detected in cerebral infarction, and I/R group was widely visible white The color of infarction lesions, compared with sham operation group, infarction area expanded significantly (PO.Q1). The infarct area of phloretin groups compared with I/R group were significantly decreased, the difference was statistically significant (P0.05) changes of cerebral edema in.4.: sham operation group, the brain water content of normal, I/R compared with the sham group, brain edema (P0.01) root bark. The degree of brain edema in each group was significantly decreased than I/R group (P0.05).5. superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GSH-PX), malondialdehyde (MDA) activity: 24 hours after reperfusion, compared with sham operation group, I/R group, superoxide dismutase and glutathione. Glutathione peroxidase levels were significantly lower (P0.01). Phloretin treatment group of superoxide dismutase, glutathione and glutathione peroxidase levels while decreased than those of sham operated group, but significantly higher than that in I/R group (P0.05) in.I/R group compared with the sham group, MDA activity of Ming Dynasty Xian Shenggao (P0.01). Phloretin intervention group compared with the sham group, MDA level increased, but less than the I/R group decreased significantly (P0.05).6.RT-PCR and Western blot showed that the expression of mRNA and protein levels of I / R group Nrf2 is higher than sham operated group (P0.05). Phloretin treatment group Nrf2 mRNA the mRNA and protein level of I / R group increased significantly (P0.05). The nerve function caused by brain injury and brain edema obviously 1. cerebral ischemia / reperfusion, superoxide dismutase.2. cerebral infarction cerebral ischemia / reperfusion resulted, glutathione and glutathione peroxidase levels were significantly decreased, while MDA levels were significantly increased. There are significant differences in the level of representation, ischemia / reperfusion resulted in decreased brain antioxidant capacity and oxidative stress in.3. group obviously phloretin after intervention compared with 1dR group rats brain nerve function score decreased significantly, the difference was statistically Meaning that phloretin can damage nerve function.4. phloretin rats cerebral edema and cerebral infarction area was significantly reduced compared with I/R group after ischemia / reperfusion resulted, that phloretin intervention significantly reduce cerebral edema after cerebral ischemia / reperfusion in rats, ultra dismutase cerebral infarction.5. root bark after the intervention of element oxides, glutathione and glutathione peroxidase levels were significantly higher than those in I/R group, that phloretin can improve the antioxidant capacity of brain tissue in the ischemia / reperfusion of the root bark of.6. in after the intervention of the content of MDA was significantly lower than that in I/R group, compared with statistical significance, that phloretin can alleviate cerebral ischemia / mRNA protein and reperfusion induced oxidative stress in.7.I/R group the expression of Nrf2 is stronger than the sham group, the difference was statistically significant, that stimulus activates Nrf2 gene expression.8. phloretin as cerebral ischemia / reperfusion The expression of mRNA protein and Nrf2 in the intervention group increased significantly compared with I/R group, the difference was statistically significant, that phloretin can upregulate the expression of Nrf2 gene. The above results can be seen, cerebral ischemia / reperfusion process significantly damaged by oxidative stress, and the intervention of phloretin can inhibit cerebral ischemia and oxidation the stress response during reperfusion injury, improve the antioxidant level, so as to improve the cerebral ischemia reperfusion injury caused by brain damage and brain function score. While regulation of oxidative stress and Nrf2 expression indicating function change and nerve enzyme score decreased, tissue damage to reduce synchronization, so we think, known as root bark may regulate Nrf2 pathway the oxidative stress resulting in rat cerebral ischemia / reperfusion injury and oxidative stress in the brain plays a neuroprotective role.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R743

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