本文關鍵詞：干預Rac1活性在大鼠心臟驟停全腦缺血模型中的腦保護作用　出處：《中南大學》2014年博士論文　論文類型：學位論文

  更多相關文章： 缺血再灌注 心臟驟停 Rac1 遲發(fā)性神經(jīng)元死亡 缺血再灌注 腦 Rac1 NSS 氧化應激 Morris水迷宮 缺血再灌注 Rac1 Trx2 Prx3 線粒體抗氧化酶

【摘要】：由各種疾病(腦卒中、微血栓、腦血管痙攣和硬化、腦血液動力學改變、頸部動脈疾病或椎動脈受壓等)或手術(嚴重顱腦外傷手術、控制性降壓、顱內(nèi)動脈瘤夾閉術、冠狀動脈旁路移植術以及頸動脈血管移植術、蛛網(wǎng)膜下腔出血等)所介導的全部或局部的腦組織短暫缺血,缺血腦組織恢復血流灌注后,腦組織損傷反而加重稱為腦缺血再灌注損傷(ischemia-reperfusion injury, I/R)。 神經(jīng)細胞對缺血性損害非常敏感,長時間的缺血打擊可導致神經(jīng)細胞大量死亡,難以再生,從而留下許多嚴重甚至是不可逆的后遺癥。因此,如何實現(xiàn)圍術期腦保護一直是臨床麻醉醫(yī)師追求的目標。研究某種能夠調(diào)動機體的內(nèi)源性保護機制,提高神經(jīng)細胞對缺血性損害的抵抗力,減少嚴重缺血導致的損傷,保證再灌注后神經(jīng)細胞的正常生理功能,是缺血性腦病治療上的一個重要策略。探求腦缺血再灌注損傷的發(fā)病機制、尋找可減輕或預防腦缺血再灌注損傷的方法或藥物,已成為近年來神經(jīng)科學領域廣大科研工作者致力的研究目標。 全腦缺血后活性氧尤其是氧自由基所引起的連鎖反應是神經(jīng)元受損的核心病理環(huán)節(jié)。Rac1蛋白被認為是還原型煙酰胺腺嘌呤二核苷酸磷酸氧化酶的生物調(diào)控開關,當有外源性的刺激因素存在時,Rac1與GDP脫離,并與三磷酸鳥苷GTP相結(jié)合而活化,隨后激活NADPH氧化酶從而產(chǎn)生活性氧簇。目前一些腦缺血再灌注研究發(fā)現(xiàn)在各種手段作用下降低Rac1活性將避免產(chǎn)生過多的活性氧參與腦缺血后神經(jīng)元的死亡或凋亡,但是針對Rac1在全腦缺血中的作用及其信號轉(zhuǎn)導的調(diào)節(jié)機制方面的研究仍然較少,其信號轉(zhuǎn)導通路在腦損傷后是否受到其他因素的影響目前尚未明確,作為活性氧產(chǎn)生通路上的“開關分子’Rac1與線粒體的抗氧化酶系統(tǒng)是否有相關調(diào)節(jié)機制參與腦缺血再灌注損傷還需進一步探索。 本實驗首先利用食道電極建立心室停搏CA(cardiac arrest)全腦缺血GCI(global cerebral ischemia)模型,并在全腦缺血15min前經(jīng)側(cè)腦室注射Rac1特異抑制劑NSC23766(50μg),觀察記錄大鼠9天內(nèi)生存情況,通過Niss1染色評價大鼠海馬CA1區(qū)在腦缺血再灌注后神經(jīng)元形態(tài)學改變,觀察其中存活神經(jīng)元密度。TUNEL染色檢測48h海馬CA1區(qū)的神經(jīng)元細胞的凋亡情況,觀察側(cè)腦室注射Rac1特異抑制劑NSC23766是否可減輕GCI后海馬神經(jīng)元損傷,證明該模型可以一定程度模擬臨床各種原因?qū)е碌男呐K停搏引發(fā)的嚴重全腦缺血損害；NADPH氧化酶“開關分子’Rac1與全腦缺血再灌損傷有關。 第二部分以此模型為基礎研究抑制Rac1活性對大鼠CA后腦神經(jīng)功能和氧化應激的影響,通過側(cè)腦室注射Rac1活性抑制劑NSC23766,于CA/GCI后30min、3h、6h、1d、3d時取海馬CA1區(qū)組織檢測Rac1總量及活化蛋白含量,從WB水平驗證側(cè)腦室注射NSC23766對Rac1活性的影響,通過改良NSS評分和Morris水迷宮檢測空間學習與記憶能力的等神經(jīng)功能改變,檢測超氧化物歧化酶(SOD)、丙二醛(MDA)等指標來反映神經(jīng)元的氧化應激水平,結(jié)果證明抑制Rac1活性對全腦缺血再灌損傷后大鼠空間學習及記憶能力有保護作用,同時抑制Rac1活性可降低神經(jīng)元氧化應激水平,提示抑制Rac1活性所產(chǎn)生的神經(jīng)保護作用與降低神經(jīng)元氧化應激水平有關。 第三部分則于CA/GCI后再灌注6h、1d、3d、5d各時間點檢測大鼠海馬CA1區(qū)Trx2, Prx3的蛋白時間表達分布水平,研究線粒體抗氧化酶Trx2, Prx3在Rac1抑制劑處理后大鼠腦缺血再灌注損傷中的變化,探討機體清除氧化產(chǎn)物的還原能力特別是線粒體抗氧化酶系統(tǒng)是否被輔助激活,關注抑制Rac1活性所產(chǎn)生的腦保護作用是否與激活、增強神經(jīng)元細胞的抗氧化酶系統(tǒng)清除活性氧能力有關。我們進一步研究線粒體抗氧化酶在全腦缺血再灌注的保護機制,期望為防治全腦I/R損傷提供新的治療靶點。 實驗發(fā)現(xiàn)：①抑制Rac1活性可明顯減少缺血再灌注所導致的遲發(fā)性神經(jīng)元死亡及錐體神經(jīng)細胞凋亡,并可以使大鼠的空間學習和記憶能力的減退得到明顯改善,起到在全缺血再灌注損傷中的神經(jīng)保護作用。②使用Rac1抑制劑NSC23766降低Racl活性對大鼠再灌注損傷的腦保護作用與改善氧化應激水平及氧化應激的腦組織相關蛋白分子相關聯(lián)。③Racl活性抑制劑處理后減輕大鼠腦缺血再灌注損傷降低組織氧化應激水平的機制可能與腦組織線粒體抗氧化酶Trx2.Prx3表達無關。 本研究為進一步闡明腦缺血再灌注損傷的機制奠定理論基礎,也為Rac1與線粒體抗氧化酶Trx2, Prx3在缺血性腦損傷的重要作用提供理論依據(jù)和治療策略,同時嘗試為治療臨床缺血性腦病提供一條新的思路。 第一部分抑制Racl活性對大鼠經(jīng)食道致顫腦缺血模型的神經(jīng)元保護作用 摘要：目的：建立SD大鼠經(jīng)食道電刺激心臟驟停全腦缺血再灌注模型,研究側(cè)腦室注射NSC23766抑制Racl活性在該模型中的神經(jīng)元保護作用。方法：經(jīng)食道插入調(diào)搏電極至心臟水平,用恒定電流誘發(fā)心臟驟停,無干預觀察6min后進行心肺復蘇。選擇雄性SD大鼠(250-300g),隨機分為四組：Sham組,CA組,NSC組(全腦缺血15min前經(jīng)側(cè)腦室置管注射Rac1特異抑制劑NSC23766), Vehicle組。記錄各組大鼠9d內(nèi)生存情況,于I/R后2d檢測各組大鼠腦水腫情況,大鼠海馬CA1區(qū)行TUNEL染色記錄凋亡陽性細胞數(shù),I/R后9d取大鼠海馬CA1區(qū)行Nissl染色,觀察存活神經(jīng)元密度。結(jié)果：大鼠心臟驟停后全腦缺血NSC23766治療組與CA模型組相比生存率顯著提高(P0.05)。NSC組與CA組相比腦水含量減少,海馬CA1區(qū)存活神經(jīng)細胞數(shù)目增多(P0.05),遲發(fā)性神經(jīng)元死亡明顯減少(P0.05)。 結(jié)論：經(jīng)食道電刺激心臟驟停全腦缺血模型可模擬臨床心臟驟停后腦損害；抑制Rac1活性可明顯減少缺血再灌注所導致的遲發(fā)性神經(jīng)元死亡及錐體神經(jīng)細胞凋亡。 第二部分抑制Racl活性對大鼠CA后腦神經(jīng)功能和氧化應激的影響 摘要：目的：探討抑制Rac1活性對大鼠心臟驟停全腦缺血后腦神經(jīng)保護作用與氧化應激的關系。方法：經(jīng)食道插入調(diào)搏電極至心臟水平,用恒定電流誘發(fā)心臟驟停,無干預觀察6min后進行心肺復蘇制作全腦缺血再灌注模型。選擇雄性SD大鼠(250-300g),隨機分為四組：Sham組,CA組,NSC組,Vehicle組(CA前15min經(jīng)側(cè)腦室置管注射NSC23766)。于再灌注后6h、1d、2d及4d時行NSS評分；再灌注第2d各組檢測超氧化物歧化酶(SOD)、丙二醛(MDA),第7d行Morris水迷宮實驗。結(jié)果：缺血再灌注后6小時大鼠海馬CA1區(qū)Racl活性明顯高于假手術組(P0.05)。同CA組相比,NSC組缺血再灌注后6h大鼠海馬CA1區(qū)Racl活性顯著降低,改良NSS評分各時間點都降低,Morris水迷宮實驗中缺血再灌后第7天和第8天搜索安全島平臺潛伏期、運動軌跡有明顯改善,空間探索試驗時NSC組第2象限停留時間百分比和穿越原平臺的次數(shù)明顯增加(P0.05)。氧化應激檢測結(jié)果顯示,缺血再灌發(fā)生時抗氧化物質(zhì)SOD降低而脂質(zhì)氧化標志物MDA升高,NSC組與CA組相比水平升高,MDA水平降低(P0.05)。結(jié)論：抑制Rac1活性在大鼠經(jīng)食道電刺激心臟驟停全腦缺血模型中可以通過降低氧化應激水平,改善大腦缺血再灌注的神經(jīng)功能損傷,發(fā)揮其在全腦I/R損傷中的神經(jīng)保護作用。 第三部分線粒體抗氧化酶Trx2, Prx3在大鼠腦缺血再灌注損傷中的變化 摘要：目的：通過評價線粒體抗氧化酶Trx2, Prx3在Rac1抑制劑處理后大鼠腦缺血再灌注損傷中的蛋白表達變化,探討線粒體抗氧化酶在大鼠腦缺血再灌注損傷的可能保護機制。方法：經(jīng)食道插入調(diào)搏電極至心臟水平,用恒定電流誘發(fā)心臟驟停CA,無干預觀察6min后進行心肺復蘇制作全腦I/R模型。選擇雄性SD大鼠(250-300g),隨機分為四組：Sham組,CA組,NSC組(全腦缺血15min前經(jīng)側(cè)腦室注射Rac1特異抑制劑NSC23766), Vehicle組。于再灌注后6h、1d、3d、5d取海馬CA1區(qū)組織行Western blot檢測硫氧還蛋白酶Trx2及線粒體過氧化氫酶Prx3的表達。結(jié)果：CA組Trx2與Prx3在缺血再灌注1d后表達穩(wěn)定,兩種蛋白與CA組6h時表達相比均有差異(P0.05),與3d表達無統(tǒng)計學差異；NSC組與CA組比較,Trx2、Prx3蛋白表達差異無統(tǒng)計學意義。結(jié)論：Rac1抑制劑處理后減輕大鼠腦缺血再灌注損傷的機制可能與腦組織線粒體抗氧化酶Trx2、Prx3表達調(diào)節(jié)無關。
[Abstract]:By a variety of diseases (stroke, micro thrombosis, cerebral vasospasm and cerebral hemodynamic changes, atherosclerosis, carotid artery disease or vertebral artery compression) or surgery (severe craniocerebral trauma surgery, controlled hypotension, intracranial aneurysm surgery, coronary artery bypass grafting and carotid artery transplantation, subarachnoid hemorrhage etc.) mediated by all or part of the brain ischemia, ischemia reperfusion, brain damage aggravate called cerebral ischemia reperfusion injury (ischemia-reperfusion, injury, I/R).
Nerve cells are very sensitive to ischemic damage, long time ischemia can lead to a large number of dead neural cells to regenerate, leaving many serious and even irreversible sequelae. Therefore, how to realize the perioperative brain protection has been a clinical anesthesiologists in the pursuit of the goal. Some research can arouse the endogenous protective mechanism of organism, improve resistance force of nerve cells to ischemic injury, reduce the severity of ischemic damage, ensure the normal physiological function of nerve cells after reperfusion, is an important strategy for the treatment of ischemic encephalopathy. Look for cerebral ischemia reperfusion injury, for reducing or preventing cerebral ischemia reperfusion injury or drug, has been become the research target in recent years the field of neuroscience researchers working.
After cerebral ischemia especially active oxygen oxygen free radical chain reaction is caused by the damaged neurons of the core pathology link.Rac1 protein is considered to be the biological control switch also reduced nicotinamide adenine dinucleotide phosphate oxidase, when the presence of exogenous stimuli, Rac1 and GDP from, and combined with three GMP and GTP activation and subsequent activation of NADPH oxidase to generate reactive oxygen species. Some studies found that cerebral ischemia reperfusion decreased Rac1 activity in a variety of means under the action to avoid excessive generation of reactive oxygen species after cerebral ischemia and neuronal cell death or apoptosis, but the study on regulation mechanism of Rac1 in the global cerebral ischemia and signal transduction the still small, whether the signal transduction pathway under the influence of other factors is not clear in the brain after injury, as the production of reactive oxygen species on the pathway" It is necessary to further explore whether the switch molecule 'Rac1 and the mitochondrial antioxidant enzyme system have a related regulatory mechanism to participate in cerebral ischemia reperfusion injury.
This experiment firstly established esophageal electrode asystole (cardiac CA arrest GCI (global) cerebral ischemia model, and cerebral ischemia) in cerebral ischemia before 15min after intracerebroventricular injection of Rac1 inhibitor NSC23766 (50 g), observed and recorded the rats within 9 days of survival, through Niss1 staining in hippocampal CA1 evaluation rat morphologic changes of neurons in cerebral ischemia reperfusion, apoptosis of neurons was observed with.TUNEL staining density of neurons in hippocampal CA1 region of 48h detection, observation of intracerebroventricular injection of Rac1 inhibitor NSC23766 can reduce the injury of hippocampal neurons after GCI, proved that the model can serious cerebral ischemia damage to a certain extent the cause of clinical simulation all kinds of cardiac arrest caused by NADPH oxidase; "molecular switch" Rac1 with global cerebral ischemia reperfusion injury.
The second part based on the model of inhibitory effect of Rac1 activity on CA of cerebral nerve function and oxidative stress in rats, by intracerebroventricular injection of Rac1 inhibitor NSC23766, after CA/GCI 30min, 3h, 6h, 1D, 3D and CA1 region of the hippocampus tissues Rac1 and activation of total protein content, from the side effects of WB level verification intracerebroventricular injection of NSC23766 on the activity of Rac1, the modified NSS score and Morris water maze spatial learning and memory ability of the neural function, detection of superoxide dismutase (SOD), malondialdehyde (MDA) and other indicators to reflect the level of oxidative stress in neurons, results show that the inhibition of Rac1 activity has a protective effect on the brain ischemia reperfusion injury after rat spatial learning and memory ability, and inhibit the activity of Rac1 can reduce the level of oxidative stress in neurons, suggesting that the neuroprotective effect produced by inhibiting the activity of Rac1 and reduce the oxidation of neurons The level of stress is related.
The third part is on the CA/GCI after reperfusion for 6h, 1D, 3D, 5D at the time of detection of Trx2 CA1 of rat hippocampus, the expression level of Prx3 protein distribution time of mitochondrial antioxidant enzymes Trx2, Prx3 in Rac1 treated rats cerebral ischemia reperfusion injury of change, reduction ability of machine body to remove oxidation the product is especially mitochondrial antioxidant system is whether the brain protective effect of assisted activation, attention to inhibit the activity of Rac1 produced by the activation of neurons, enhance the antioxidant system of reactive oxygen scavenging capacity. We further study the protective mechanism of antioxidant enzymes in mitochondria in cerebral ischemia reperfusion, expect to provide new therapeutic targets for prevention and treatment of cerebral I/R injury.
The experiment showed that: the inhibition of Rac1 activity can significantly reduce ischemia reperfusion caused by delayed neuronal death and pyramidal neuronal apoptosis, and may cause the loss of spatial learning and memory ability of rats was obviously improved, play in the ischemia reperfusion injury in the neuroprotective effect. The use of Rac1 inhibitors reduce NSC23766 the molecular brain oxidative stress and oxidative stress and improve the protection of the activity of Racl on reperfusion injury of rat brain tissue related protein associated with mitochondrial processing. The inhibitor of Racl activity after cerebral ischemia reperfusion injury in rats reduced oxidative stress in low level of organization and possible mechanism of antioxidase in brain Trx2.Prx3 expression.
This study laid a theoretical foundation for further elucidation of the mechanisms of cerebral ischemia reperfusion injury, as well as Rac1 and mitochondrial antioxidant enzymes Trx2, Prx3 and provide a theoretical basis and treatment strategies play an important role in ischemic brain injury, and try to provide a new idea for clinical treatment of ischemic encephalopathy.
The first part inhibits the protective effect of Racl activity on the rat model of cerebral ischemia induced by the esophagus
Abstract: Objective: to establish SD rat transesophageal electrical stimulation of cardiac arrest cerebral ischemia reperfusion model, neuron protective effect of intracerebroventricular injection of NSC23766 inhibited the activity of Racl in this model. Methods: the transesophageal pacing electrode insertion to the level of the heart, with a constant current induced cardiac arrest, without intervention after 6min CPR. Select male SD rats (250-300g), were randomly divided into four groups: Sham group, CA group, NSC group (global cerebral ischemia before 15min by intraventricular catheter injection of a specific inhibitor of Rac1 NSC23766), Vehicle group. The rats were recorded. 9D internal storage, I/R 2D to detect brain edema of rats, CA1 of rat hippocampus by TUNEL staining to record the number of apoptotic cells, I/R 9D CA1 of rat hippocampus by Nissl staining to observe the survival neuron density. Results: the rat cardiac arrest after cerebral ischemia NSC23766 treatment group and CA model group. The ratio of survival increased significantly (P0.05). Compared with the CA group, the.NSC content of the brain decreased significantly, and the number of viable neurons in the CA1 area increased (P0.05), and the delayed neuronal death was significantly reduced (P0.05).
Conclusion: the esophageal electrical stimulation model of global cerebral ischemia can simulate brain damage after cardiac arrest. Inhibition of Rac1 activity can significantly reduce delayed neuronal death and pyramidal nerve cell apoptosis induced by ischemia-reperfusion.
The second part inhibits the effect of Racl activity on the nerve function and oxidative stress in the rat brain after CA
Abstract: Objective: To investigate the inhibition of Rac1 activity on cardiac arrest in rats after cerebral ischemia and neuroprotective effects of oxidative stress. Methods: the transesophageal pacing electrode insertion to the level of the heart, with a constant current induced cardiac arrest, no intervention on 6min after cardiopulmonary resuscitation for cerebral ischemia reperfusion model. Male SD rats (250-300g), were randomly divided into four groups: Sham group, CA group, NSC group, Vehicle group (CA 15min before the lateral ventricle catheter injection of NSC23766). After reperfusion, 6h, 1D, 2D and 4D were NSS score; reperfusion in 2D were detected by superoxide dismutase (SOD), malondialdehyde (MDA), the 7d Morris water maze test. Results: 6 hours after ischemia reperfusion Racl in rat hippocampal CA1 region was significantly higher than that of sham operation group (P0.05). Compared with the CA group, NSC group, Racl after ischemia reperfusion in hippocampal CA1 area of rats significantly decreased the activity of 6h. The modified NSS score Time points are reduced in Morris water maze after ischemia reperfusion for seventh days and eighth days of searching safety island platform latency, the trajectory is obviously improved, the number of space exploration test group NSC second quadrant time and percentage of crossing the original platform significantly increased (P0.05). Oxidative stress test results showed that the occurrence of ischemia reperfusion when the antioxidant SOD decreased lipid peroxidation markers MDA increased in NSC group compared with CA group increased the level of MDA decreased (P0.05). Conclusion: the inhibition of Rac1 activity in rat cardiac arrest by transesophageal electrical stimulation of cerebral ischemia model can reduce oxidative stress level, nerve function improve brain ischemia reperfusion injury in the play, the whole brain I/R injury in neuroprotective effect.
The changes of mitochondrial antioxidant enzyme Trx2 and Prx3 in the third part of cerebral ischemia reperfusion injury in rats
Abstract: Objective: To evaluate the mitochondrial antioxidant enzymes Trx2, Prx3 in Rac1 inhibitor treatment after cerebral ischemia reperfusion injury in rats. The protein expression changes of mitochondrial antioxidant enzymes in rat cerebral ischemia reperfusion injury of the possible protective mechanism. Methods: the transesophageal pacing electrode insertion to the level of the heart, with a constant current induced heart arrest CA, without intervention on 6min after cardiopulmonary resuscitation made the whole brain I/R model. Select male SD rats (250-300g), were randomly divided into four groups: Sham group, CA group, NSC group (global cerebral ischemia 15min after intracerebroventricular injection of Rac1 inhibitor NSC23766), Vehicle group after reperfusion. 6h, 1D, 3D, 5D in CA1 area of hippocampus tissue Western blot detection of thioredoxin reductase and mitochondrial Trx2 catalase Prx3 expression. Results: the expression of Trx2 and Prx3 in stable CA group 1D after reperfusion, the expression of two kinds of protein with CA group 6H The differences were compared (P0.05), there was no significant difference in the expression of 3D and NSC; compared with group CA and group Trx2, Prx3 expression had no statistical difference. Conclusion: mitochondrial Rac1 inhibitor treatment after cerebral ischemia reperfusion injury in rats and possible mechanisms of brain tissue antioxidant enzymes Trx2, Prx3 expression.

【學位授予單位】：中南大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R-332;R743

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