本文選題：缺血性中風(fēng) + 甲氟喹　； 參考：《華東師范大學(xué)》2017年碩士論文

【摘要】：缺血性中風(fēng)是一類嚴(yán)重危害人類身體健康的疾病,會引起不同程度上的腦損傷。在臨床上,一般有神經(jīng)保護(hù)以及溶栓和抗凝等治療手段,但目前對于防治腦缺血所誘發(fā)腦功能損傷的藥物治療手段并非十分理想。因此,對腦缺血所導(dǎo)致腦損傷的防治手段尚需進(jìn)一步研究。目前已知:腦缺血中風(fēng)導(dǎo)致細(xì)胞死亡的一個(gè)關(guān)鍵機(jī)制在于缺血導(dǎo)致的相關(guān)腦區(qū)的神經(jīng)過度興奮。因此,阻止腦缺血后的神經(jīng)過度興奮可望為防治缺血性中風(fēng)誘發(fā)腦細(xì)胞死亡的一個(gè)有效途徑。我們注意到:臨床用于抗瘧疾的藥物甲氟喹是電突觸阻斷劑;已有大量文獻(xiàn)報(bào)道,阻斷電突觸連接可以顯著降低神經(jīng)系統(tǒng)的興奮度,提示該藥物可能可以防止缺血中風(fēng)誘發(fā)的腦細(xì)胞死亡�；谶@一推測,本研究使用甲氟喹的左旋異構(gòu)體,在受雙側(cè)頸總動脈夾閉14分鐘的小鼠全腦缺血中風(fēng)模型上、通過觀察缺血敏感腦區(qū)海馬CA1的神經(jīng)元存活情況,探討了左旋甲氟喹對腦缺血中風(fēng)誘發(fā)腦細(xì)胞死亡的可能防治作用。我們首先通過尼氏染色的方法,在上述中風(fēng)動物模型上觀察到海馬CA1神經(jīng)元死亡。為更好地量化神經(jīng)元的存活情況,我們接下來主要采用免疫熒光染色手段、測量存活神經(jīng)元的數(shù)量。實(shí)驗(yàn)觀察到:與假手術(shù)實(shí)驗(yàn)組(即只分離勁總動脈但不結(jié)扎缺血)相比,小鼠海馬CA1神經(jīng)元的數(shù)目在頸動脈閉合缺血后的1天、3天和7天分別減少27%(P0.001)、50%(P0.001)和36%(P0.001)。隨后,我們鑒定了頸動脈閉合缺血后、腹腔即刻注射不同劑量左旋甲氟喹的可能腦保護(hù)效果,在缺血后1天的動物模型上發(fā)現(xiàn):與未接受藥物注射的模型鼠(即空白溶劑對照組)相比,接受3.5mg/kg、5.5mg/kg和7.5mg/kg左旋甲氟喹注射的小鼠海馬CA1神經(jīng)元數(shù)目分別提高了 16%(P=0.0149)、17%(P=0.0161)和23%(P0.001);并且,與非中風(fēng)模型老鼠(即假手術(shù)組)相比,3.5mg/kg給藥組神經(jīng)元數(shù)目降低15.2%(P = 0.020),7.5mg/kg給藥組神經(jīng)元數(shù)目與假手術(shù)組無顯著差異(P= 0.413),幾乎恢復(fù)到正常值。接著,我們觀察了給予左旋甲氟喹(7.5mg/kg)后的不同時(shí)間、CA1神經(jīng)元的存活情況,實(shí)驗(yàn)發(fā)現(xiàn):缺血給予藥物后的1天和3天、小鼠海馬CA1神經(jīng)元存活情況基本一致;其中,在缺血后1天,給藥組神經(jīng)元數(shù)目比溶劑組增多了 36%(P0.001),且與假手術(shù)組無顯著差異(P = 0.298);在缺血后3天,給藥組神經(jīng)元數(shù)目比溶劑組增多了 25%(P= 0.001),與假手術(shù)組無顯著差異(P= 0.368)。最后,為了鑒定在缺血后的一個(gè)較長時(shí)間給予藥物是否依然有效,我們在缺血手術(shù)后的1小時(shí)腹腔注射7.5mg/kg左旋甲氟喹,也發(fā)現(xiàn)CA1神經(jīng)元數(shù)目能基本恢復(fù)到正常水平(P= 0.169)。本論文的發(fā)現(xiàn)顯示左旋甲氟喹可以有效阻止腦缺血誘發(fā)的海馬CA1神經(jīng)元死亡,提示該藥物對缺血中風(fēng)具有潛在的腦保護(hù)作用,為臨床防治缺血性中風(fēng)誘發(fā)的腦損傷提供了一個(gè)新的可能途徑。
[Abstract]:Ischemic stroke is a kind of disease that seriously endangers the health of human body and can cause brain damage to varying degrees. In clinic, there are neuroprotective, thrombolytic and anticoagulant treatment methods, but at present, the drug therapy is not very ideal for the prevention and treatment of cerebral function injury induced by cerebral ischemia. Therefore, the prevention and treatment of brain injury caused by cerebral ischemia need further study. It is now known that one of the key mechanisms of cell death due to ischemic stroke is the neuronal hyperstimulation in the ischemic-associated brain region. Therefore, the prevention of neuronal hyperstimulation after cerebral ischemia may be an effective way to prevent and treat cerebral cell death induced by ischemic stroke. We note that mefloquine, a clinical drug used against malaria, is an electrical synaptic blocker, and that blocking electrical synaptic connections has been reported to significantly reduce the excitability of the nervous system. It suggests that the drug may prevent brain cell death induced by ischemic stroke. Based on this hypothesis, the survival of hippocampal CA1 neurons in the ischemic sensitive brain region was observed in a mouse model of global cerebral ischemic stroke after bilateral common carotid artery occlusion for 14 minutes, using the levo-isomer of mefloquine. To explore the possible preventive and therapeutic effects of levo-mefloquine on cerebral cell death induced by cerebral ischemic stroke. We first observed hippocampal CA1 neuron death in the model of apoplexy by Nissl staining. In order to better quantify the survival of neurons, we mainly use immunofluorescence staining to measure the number of surviving neurons. It was observed that the number of CA1 neurons in hippocampus decreased by 27% (P0.001) 50% (P0.001) and 36% (P0.001) respectively on the 3rd and 7th day after closed carotid artery ischemia compared with the sham-operated experimental group. Subsequently, we identified the possible protective effects of different doses of levofluraquine immediately after closed carotid ischemia. On the first day after ischemia, the number of CA1 neurons in hippocampus increased by 16% (P0. 0149) 17% (P0. 0161) and 23% (P0. 001) in mice treated with 3.5 mg / kg and 5. 5 mg / kg of 7.5mg/kg, respectively, compared with the control group without drug injection (P0. 0149), and the number of hippocampal CA1 neurons increased by 16% (P0. 0149) and 23% (P0. 001), respectively. The number of neurons in 3.5 mg / kg group decreased by 15.2% (P = 0.020) compared with that in non-apoplexy model mice (P = 0.020). There was no significant difference between the two groups (P = 0.413) and almost returned to normal value. Then, we observed the survival of CA1 neurons at different times after administration of 7.5mg/kg. The results showed that the survival of CA1 neurons in hippocampus of mice was basically the same on the 1st and 3rd day after administration of the drug after ischemia, and the survival of CA1 neurons in hippocampus of mice was basically the same. On the first day after ischemia, the number of neurons in the administration group was 36% higher than that in the solvent group (P = 0.298), and the number of neurons in the administration group was 25% more than that in the solvent group (P = 0.001) on the 3rd day after ischemia, but there was no significant difference between the administration group and the sham-operation group (P = 0.368). Finally, in order to determine whether the drug was still effective for a longer period of time after ischemia, we injected 7.5mg/kg levofloxaquine intraperitoneally at 1 hour after ischemia and found that the number of CA1 neurons returned to normal level (P = 0.169). Our findings suggest that levofluraquine can effectively prevent hippocampal CA1 neuron death induced by cerebral ischemia, suggesting that the drug has a potential cerebral protective effect on ischemic stroke. It provides a new approach for clinical prevention and treatment of cerebral injury induced by ischemic stroke.
【學(xué)位授予單位】：華東師范大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R743.3

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