本文選題：Ghrelin + 蛛網(wǎng)膜下腔出血　； 參考：《第二軍醫(yī)大學(xué)》2015年碩士論文

【摘要】：目的蛛網(wǎng)膜下腔出血,特別是動(dòng)脈瘤破裂導(dǎo)致的蛛網(wǎng)膜下腔出血是一種致死率和致殘率很高的疾病,蛛網(wǎng)膜下腔出血導(dǎo)致的中風(fēng),占中風(fēng)總數(shù)的5-7%,腦血管痙攣和早期腦損傷是蛛網(wǎng)膜下腔出血患者通常要面臨的兩個(gè)主要并發(fā)癥,在研究初期研究人員主要把他們的精力集中在腦血管痙攣的研究上,并認(rèn)為這可能是導(dǎo)致蛛網(wǎng)膜下腔出血患者預(yù)后不佳的主要原因。為了阻止腦血管痙攣導(dǎo)致的二次腦損傷,研究人員進(jìn)行了很多的動(dòng)物實(shí)驗(yàn)和臨床試驗(yàn),當(dāng)腦血管痙攣被很好的控制之后,人們發(fā)現(xiàn)并沒(méi)有能很好的改善蛛網(wǎng)膜下腔出血患者的預(yù)后。近年來(lái)研究發(fā)現(xiàn),早期腦損傷(early brain injury EBI)可能是導(dǎo)致蛛網(wǎng)膜下腔出血患者預(yù)后不佳的重要原因。應(yīng)此,探索蛛網(wǎng)膜下腔出血后早期腦損傷的發(fā)生機(jī)制,尋找有效的治療手段很有必要。Ghrelin是一種含有28個(gè)氨基酸的多肽,是人類發(fā)現(xiàn)的第一個(gè)生長(zhǎng)激素促分泌素的內(nèi)源性配體,通過(guò)與生長(zhǎng)激素促分泌素受體結(jié)合促進(jìn)生長(zhǎng)激素的釋放發(fā)揮廣泛的生物學(xué)作用,循環(huán)中的Ghrelin主要來(lái)源于胃腸道,其中大部分由胃粘膜的X/A細(xì)胞分泌,除胃腸道外Ghrelin也廣泛分布于人、大鼠等多種動(dòng)物的中樞神經(jīng)系統(tǒng)和外周組織器官,如：下丘腦、垂體、心肌、胎盤及睪丸等。研究發(fā)現(xiàn)Ghrelin可以通過(guò)多種機(jī)制發(fā)揮神經(jīng)保護(hù)功能,而P13K/Akt信號(hào)通路可能在其中發(fā)揮重要作用。本實(shí)驗(yàn)通過(guò)觀察Ghrelin在大鼠蛛網(wǎng)膜下腔出血后早期腦損傷中的保護(hù)作用,并探討其保護(hù)作用機(jī)制,為臨床治療蛛網(wǎng)膜下腔出血,特別是早期腦損傷提供新的思路和方法。方法100只2月齡清潔級(jí)SD雄性大鼠,體重250-300g,隨機(jī)分為5組：(1)假手術(shù)組(n=20);(2)SAH模型組(n=20)；(3)SAH+溶劑組(n=20)；(4)SAH+Ghrelin組(n=20)；(5)SAH+Ghrelin+Ly294002組(n=20)。采用自體血視交叉池注射法制作大鼠蛛網(wǎng)膜下腔出血模型；假手術(shù)組穿刺針插入視交叉池,但不注入血液；SAH+溶劑組注血后立刻和注血后1h分別向腹腔注射雙蒸水0.5ml;SAH+Ghrelin組于注血后立刻和注血后1h分別向大鼠腹腔注射相應(yīng)濃度Ghrelin水溶液0.5ml;SAH+Ghrelin+Ly294002組于注血前0.5h左側(cè)腦室注射Ly294002溶液(50mmol/L溶于DMSO濃度為25%的磷酸鹽緩沖液)10gL;各組分別于術(shù)后24小時(shí)采用Yamaguchi評(píng)分系統(tǒng)對(duì)大鼠神經(jīng)功能缺損情況進(jìn)行評(píng)分,并處死大鼠,干濕重比值法測(cè)大鼠腦含水量；TUNEL檢測(cè)各實(shí)驗(yàn)組大鼠顳葉皮層神經(jīng)元細(xì)胞凋亡情況；免疫熒光檢測(cè)p-Akt在大鼠顳葉的表達(dá);western blot檢測(cè)各組大鼠顳葉p-Akt, caspase-3兩種蛋白表達(dá)情況。結(jié)果在蛛網(wǎng)膜下腔出血后24小時(shí)Ghrelin可以明顯改善大鼠的神經(jīng)功能,減少神經(jīng)細(xì)胞的凋亡以及減輕腦水腫。免疫熒光圖片顯示p-Akt的表達(dá)主要是在神經(jīng)元內(nèi)。Ghrelin的應(yīng)用可以在蛛網(wǎng)膜下腔出血后激活神經(jīng)元內(nèi)PI3K/Akt信號(hào)通過(guò)路,促進(jìn)神經(jīng)元內(nèi)p-Akt的表達(dá),從而抑制下游caspase-3蛋白的表達(dá)而發(fā)揮神經(jīng)保護(hù)作用的。Ghrelin的這種神經(jīng)保護(hù)作用可以被PI3K/Akt信號(hào)通路的特異性抑制劑LY294002抑制。結(jié)論早期腦損傷是蛛網(wǎng)膜下腔出血預(yù)后不佳的重要原因之一,Ghrelin可以有效的減輕蛛網(wǎng)膜下腔出血后早期腦損傷,其機(jī)制可能是通過(guò)激活神經(jīng)元內(nèi)PI3K/Akt信號(hào)通路實(shí)現(xiàn)的。
[Abstract]:Objective the subarachnoid hemorrhage, especially the subarachnoid hemorrhage caused by aneurysm rupture, is a disease with high mortality and high disability. The stroke caused by subarachnoid hemorrhage, 5-7% of the total number of strokes, cerebral vasospasm, and early brain injury are two major complications that patients usually face in subarachnoid hemorrhage. The researchers focused their efforts on the study of cerebral vasospasm, which could be the main cause of poor prognosis in patients with subarachnoid hemorrhage. In order to prevent the two brain damage caused by cerebral vasospasm, the researchers carried out a lot of experiments and clinical trials, when cerebral vasospasm was very high. After good control, people have found that there is no good improvement in the prognosis of patients with subarachnoid hemorrhage. In recent years, it has been found that early brain damage (early brain injury EBI) may be an important cause of poor prognosis in subarachnoid hemorrhage patients. Finding effective treatment means that.Ghrelin is a polypeptide containing 28 amino acids. It is an endogenous ligand for the first growth hormone secretin found by human beings. It plays a broad biological role by combining with the growth hormone secretin receptor to promote the release of growth hormone. The circulating Ghrelin is mainly derived from the gastrointestinal tract. Most of them are secreted by the X/A cells of the gastric mucosa. Besides the gastrointestinal tract, Ghrelin is also widely distributed in the central nervous system and peripheral tissues of a variety of animals, such as the hypothalamus, the pituitary, the myocardium, the placenta and the testis, and so on. It is found that Ghrelin can play a neuroprotective function through a variety of mechanisms, while the P13K/Akt signaling pathway can be used. The protective effect of Ghrelin on early brain injury after subarachnoid hemorrhage in rats was observed and its protective mechanism was explored to provide new ideas and methods for clinical treatment of subarachnoid hemorrhage, especially early brain injury. 100 2 month old clean grade SD male rats and weight 250- in Fang method. 300g, randomly divided into 5 groups: (1) sham operation group (n=20); (2) SAH model group (n=20); (3) SAH+ solvent group (n=20); (4) SAH+Ghrelin group (n=20); (5) SAH+Ghrelin+Ly294002 group (n=20). The rat subarachnoid hemorrhage model was made by autologous blood optic cross pool injection; the puncture needle was inserted into the optic cross pool, but not the blood; SAH+ 0.5ml was injected into the abdominal cavity immediately after the blood injection of the solvent group and the 1H injected after the blood injection, and the group SAH+Ghrelin was injected with the corresponding concentration of 0.5ml in the abdominal cavity of the rats after the injection of blood and 1h after the injection of blood, respectively. The SAH+Ghrelin+Ly294002 group injected the Ly294002 solution in the left ventricle of 0.5h before the injection of blood (50mmol/L dissolved in the phosphate of DMSO concentration of 25%. Yamaguchi score system was used to score the nerve function defect in rats 24 hours after the operation, and the rats were killed and the rat brain water content was measured by the dry wet weight ratio method. TUNEL was used to detect the neuronal apoptosis in the temporal cortex of the rats in each experimental group; the expression of p-Akt in the temporal lobe of rats was detected by immunofluorescence; western Blot was used to detect the expression of p-Akt and caspase-3 two proteins in the temporal lobe of rats. Results in the 24 hours after subarachnoid hemorrhage Ghrelin could obviously improve the nerve function of rats, reduce the apoptosis of the nerve cells and reduce the brain edema. The expression of p-Akt is mainly in the application of.Ghrelin in the neuron. After the subomental hemorrhage, the PI3K/Akt signal in the neuron activates the signal through the neuron to promote the expression of p-Akt in the neuron, thus inhibiting the expression of the downstream caspase-3 protein and the neuroprotective effect of.Ghrelin, which can be suppressed by the specific inhibitor of the PI3K/Akt signaling pathway, LY294002. Conclusion early brain damage is a spider web. One of the important reasons for the poor prognosis of submembrane hemorrhage, Ghrelin can effectively reduce the early brain damage after subarachnoid hemorrhage, and its mechanism may be realized by activating the PI3K/Akt signal pathway in the neuron.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：R651.12

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