【摘要】：由血管損傷和炎癥引起的認知障礙影響著大腦功能。研究已經(jīng)證實,認知障礙與血管性損傷、炎癥直接關(guān)聯(lián),而損傷程度與炎癥、血管性損傷呈正相關(guān)。研究表明,大腦在認知功能上發(fā)揮著自已的特殊作用,全面的大腦保護可能在急性心肌缺血再灌注損傷的情況下,有助于降低患者的認知障礙。七氟醚對抗心肌和腦損傷能起到積極的作用,因為它有助于降低心肌耗氧量,抑制心肌鈣離子的運動,激活線粒體信號傳導(dǎo)通路,并且阻止炎癥因子的產(chǎn)生。目前對于血管損傷的治療主要依賴于手術(shù)與麻醉的聯(lián)合治療,然而,關(guān)于七氟醚在急性心肌缺血再灌注損傷導(dǎo)致的認知障礙治療方面的效果,沒有直接的和系統(tǒng)化的驗證。在本研究中,我們設(shè)法確定麻醉劑七氟醚和芬太尼對于大鼠腦組織長期認知功能的影響,以及和炎性因子如血管內(nèi)皮生長因子(VEGF)、白介素-1β (IL-1β)和腫瘤壞死因子-α (TNF-α)潛在的相關(guān)性。我們使用穿梭箱和水迷宮測試去研究Wistar大鼠的認知功能。結(jié)果表明,經(jīng)過七氟醚或芬太尼治療的大鼠同急性心肌缺血再灌注大鼠模型相比,電擊次數(shù)更少并且有更多的主動逃生次數(shù)。麻醉劑的治療也縮短學(xué)習(xí)和記憶的周期,這表明了麻醉劑在認知功能方面的保護作用。此外,我們的研究結(jié)果揭示在使用麻醉藥的大鼠頭部組織中TNF-α和IL-1β表達降低而VEGF表達升高。這些發(fā)現(xiàn)強調(diào)了通過調(diào)節(jié)炎癥因子的表達,七氟醚和芬太尼在急性心肌缺血再灌注損傷老齡大鼠的認知功能恢復(fù)中發(fā)揮著改善作用。與微血管損傷相關(guān)的缺血組織再灌注是炎癥反應(yīng)活化的直接后果。臨床治療血管損傷的主要方法是手術(shù)結(jié)合麻醉,常規(guī)的麻醉劑如丙泊酚可能引起自主認知功能障礙,不利于血管損傷后認知障礙的康復(fù)。所以我們計劃通過動物實驗的方法,對于七氟醚和芬太尼對急性心肌缺血再灌注損傷的老齡大鼠大腦的保護作用進行調(diào)查。前期研究中,我們認為七氟醚和芬太尼在上調(diào)VEGF表達,降低TNF-α和IL-1β表達水平時,可能有助于老齡大鼠術(shù)后認知功能損害的康復(fù)。本研究擬從分子機制方面探討七氟醚和芬太尼對老齡大鼠認知功能的影響,探討其對認知功能的保護機制。120只Wistar大鼠隨機分為四組,A組大鼠接受假手術(shù),B組大鼠為急性心肌缺血再灌注模型,C組為B組的基礎(chǔ)上吸入七氟醚,D組在B組的基礎(chǔ)上靜脈注射芬太尼。采用TUNEL檢測Wistar大鼠海馬神經(jīng)元細胞凋亡指數(shù),采用流式細胞術(shù)測定海馬神經(jīng)元的凋亡率和胞漿內(nèi)鈣離子水平。再利用熒光探針測定鼠海馬神經(jīng)元胞漿中線粒體的膜電位情況。酶聯(lián)免疫吸附試驗(ELISA)測定大鼠心尖血液中炎癥因子的含量。測定各組經(jīng)前述方法分離提純的海馬神經(jīng)元細胞勻漿內(nèi)線粒體呼吸鏈復(fù)合物活性。使用麻醉藥的大鼠血液中TNF一α和IL-1β表達降低而VEGF表達升高。麻醉劑的治療降低了神經(jīng)元凋亡率和凋亡指數(shù),減輕了缺血時鈣離子向神經(jīng)元細胞內(nèi)的轉(zhuǎn)移,提高了神經(jīng)元胞漿內(nèi)線粒體膜電位活性和線粒體呼吸鏈復(fù)合物Ⅰ～Ⅳ活性。麻醉劑可以有效減輕老齡大鼠因急性心肌缺血再灌注損傷造成的認知功能障礙,其機制與提高VEGF表達水平,促進新生血管形成過程,減輕炎癥因子所參與的對海馬神經(jīng)元細胞所造成的炎性損傷有關(guān)。此外,麻醉劑還能夠減輕海馬神經(jīng)元內(nèi)氧化應(yīng)激過程,從而減少了海馬神經(jīng)元細胞凋亡,減輕了認知功能障礙的發(fā)生。
[Abstract]:Cognitive disorders caused by vascular injury and inflammation affect the brain function. The study has confirmed that cognitive impairment is directly related to vascular injury and inflammation, and the degree of injury is positively related to inflammation and vascular injury. The study shows that the brain plays a special role in the cognitive function, and the comprehensive brain protection can help to reduce the cognitive disorder of the patient under the condition of acute myocardial ischemia-reperfusion injury. Sevoflurane can play a positive role in the fight against myocardial and brain damage, as it helps to reduce the oxygen consumption of the myocardium, inhibit the movement of the calcium ions in the myocardium, activate the mitochondrial signaling pathway, and prevent the generation of inflammatory factors. At present, the treatment of vascular injury mainly depends on the combination of operation and anesthesia. However, the effect of sevoflurane on the treatment of cognitive impairment caused by reperfusion injury of acute myocardial ischemia is not directly and systematically verified. In this study, we managed to determine the effects of anesthetic sevoflurane and fentanyl on the long-term cognitive function of brain tissue in rats, as well as the potential correlation of inflammatory factors such as vascular endothelial growth factor (VEGF), interleukin-1 (IL-1), and tumor necrosis factor-1 (TNF-1). We used the shuttle box and the water maze test to study the cognitive function of the Wistar rats. The results showed that compared with the model of acute myocardial ischemia-reperfusion in rats treated with sevoflurane or fentanyl, the number of electric shock was less and the number of active escape was more. The treatment of the anesthetic also shortens the cycle of learning and memory, which shows the protective effect of the anesthetic in the cognitive function. In addition, our findings reveal a decrease in the expression of TNF-1 and IL-1 in the head tissue of a rat using an anesthetic, while the expression of VEGF is increased. These findings highlight the improvement in the recovery of cognitive function in aged rats by modulating the expression of inflammatory factors, sevoflurane and fentanyl. Ischemia-reperfusion associated with microvascular injury is a direct consequence of inflammatory response activation. The main method of the clinical treatment of vascular injury is to combine the operation with the anesthesia, and the conventional anesthetic such as propofol may cause the self-cognitive dysfunction, which is not conducive to the rehabilitation of the cognitive disorder after the vascular injury. So we plan to investigate the protective effect of sevoflurane and fentanyl on the brain of aged rats with acute myocardial ischemia-reperfusion injury through the method of animal experiment. In the earlier study, we think that sevoflurane and fentanyl may be helpful to the recovery of cognitive function impairment in aged rats at the time of up-regulation of the expression of VEGF, the reduction of the level of TNF-1 and IL-1. In this study, the effects of sevoflurane and fentanyl on the cognitive function of aged rats were discussed from the aspects of molecular mechanism, and the protection mechanism for cognitive function was discussed.120 Wistar rats were randomly divided into four groups. In group C, the group B was given a group B, and the group B was given fentanyl on the basis of group B. TUNEL was used to detect the apoptosis index of the rat hippocampal neurons, and the apoptosis rate and the intracellular calcium ion level of the hippocampal neurons were measured by flow cytometry. The membrane potential of the mitochondria in the rat hippocampal neurons was determined by using the fluorescence probe. Enzyme-linked immunosorbent assay (ELISA) was used to determine the content of inflammatory factors in the apical blood of the rat. The activity of the mitochondrial respiratory chain complex in the homogenate of the cultured hippocampal neurons was determined by the above method. The expression of TNF-1 and IL-1 in the blood of rats using the anesthetic was decreased and the expression of VEGF was increased. The treatment of the anesthetic reduces the neuron apoptosis rate and the apoptosis index, reduces the transfer of the calcium ions to the neuron cells during the ischemia, and improves the mitochondrial membrane potential activity and the mitochondrial respiratory chain complex I-IV activity in the neuron cytoplasm. The anesthetic can effectively relieve the cognitive dysfunction caused by acute myocardial ischemia-reperfusion injury in the aged rats, and the mechanism is related to the improvement of the expression level of the VEGF, the promotion of the formation of the new blood vessel and the reduction of the inflammatory injury caused by the inflammatory factors involved in the hippocampal neuronal cells. In addition, the anesthetic can reduce the oxidative stress in the hippocampal neurons, thereby reducing the apoptosis of the hippocampal neurons and reducing the occurrence of cognitive dysfunction.
【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】：R614.2

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相關(guān)期刊論文 前9條

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