【摘要】：目的:在細胞水平考察AE-624對LPS誘導(dǎo)的PC12細胞損傷的保護作用。在動物水平研究AE-624對鏈脲佐菌素(STZ)側(cè)腦室注射誘導(dǎo)的AD模型小鼠認知行為的影響,并探討相關(guān)機制。方法:(1)以200μg/m L的LPS誘導(dǎo)PC12細胞建立損傷模型,并以5,10,20,40,60,80,100μg/m L的AE-624拮抗其作用,采用四甲基偶氮唑鹽(MTT)法檢測各組細胞存活率。(2)將昆明小鼠或BALB/c鼠按體重隨機分為正常組,模型組,陽性對照組(Donepezil組),AE-624低、中、高劑量組。除正常組小鼠注射PBS外,其余各組均側(cè)腦室注射STZ(30μg/μL,5μL)制備AD模型。然后給予5,15,45mg/kg的AE-624溶液灌胃15天。給藥完成后,利用自主活動、新物體識別、O迷宮、水迷宮等行為學(xué)實驗測試小鼠的認知行為,通過LTP實驗觀察AE-624對突觸可塑性的影響,通過測定血清和海馬組織內(nèi)SOD活力、MDA含量觀察AE-624對氧化作用的影響,通過尼氏染色觀察AE-624對小鼠神經(jīng)元的影響。結(jié)果:(1)細胞實驗表明,AE-624給藥組細胞存活率顯著高于模型組(P0.05或P0.005),說明其對LPS誘導(dǎo)的PC12細胞損傷有明顯的保護作用。(2)與模型組相比,AE-624給藥組小鼠的認知行為有明顯提高:其自主活動性增加(P0.05),新物體識別優(yōu)先指數(shù)升高(P0.05),在O迷宮中開臂區(qū)域的時間明顯增加(P0.05或P0.01),在水迷宮測試期逃避潛伏期明顯縮短(P0.01或P0.005)。LTP有明顯提高:AE-624給藥組PS波增幅顯著高于模型組(P0.05)。與正常組相比,模型組小鼠血清和海馬組織內(nèi)SOD活力明顯降低(P0.05),MDA含量明顯升高(P0.001)。與模型組相比,AE-624組在給藥后能明顯提高小鼠血清和海馬組織SOD活力(P0.05或P0.001),降低血清和海馬組織MDA含量(P0.05或P0.001)。尼氏染色發(fā)現(xiàn),與正常組相比,模型組小鼠神經(jīng)元數(shù)目明顯減少(P0.01),與模型組相比,AE-624可以明顯增加小鼠海馬區(qū)神經(jīng)元數(shù)目(P0.05),對模型小鼠海馬區(qū)神經(jīng)元有明顯的保護作用。結(jié)論:(1)AE-624對LPS誘導(dǎo)的PC12細胞損傷有明顯的保護作用。(2)AE-624對鏈脲佐菌素(STZ)誘導(dǎo)的AD模型小鼠認知功能具有明顯保護作用,其保護作用機制可能與AE-624的抗氧化作用、抗神經(jīng)元凋亡以及提高小鼠海馬PP-DG區(qū)的LTP,改善模型小鼠突觸可塑性有關(guān)。
[Abstract]:Aim: to investigate the protective effect of AE-624 on PC12 cell injury induced by LPS at cell level. The effects of AE-624 on the cognitive behavior of AD model mice induced by streptozotocin (STZ) lateral ventricle injection were studied at the animal level, and the related mechanisms were discussed. Methods: (1) PC12 cells were induced by 200 渭 g / mL LPS, and the cells were antagonized by AE-624 of 50 渭 g / mL. The survival rate of each group was detected by (MTT). (2) Kunming mice or BALB/c mice were randomly divided into normal group and model group according to their body weight. The positive control group (Donepezil group) had low, medium and high dose AE 624. With the exception of normal mice, the other groups were injected with STZ (30 渭 g / 渭 L, 5 渭 L) to make AD model. Then the rats were given a 45 mg / kg AE-624 solution for 15 days. After administration, the cognitive behavior of mice was tested by behavioral experiments such as self-activity, new object recognition, water maze and so on. The effect of AE-624 on synaptic plasticity was observed by LTP experiment. The effect of AE-624 on oxidation was observed by measuring the activity of SOD in serum and hippocampal tissue, and the effect of AE-624 on mouse neurons was observed by Nissl staining. Results: (1) the cell survival rate of AE-624 group was significantly higher than that of model group (P0.05 or P0.005), which indicated that it had obvious protective effect on PC12 cell injury induced by LPS. (2) compared with model group, the cognitive behavior of mice in AE-624 group was significantly higher than that in model group (P0.05 or P0.005). Increased autonomous activity (P0.05), increased priority index for new object recognition (P0.05), increased time to open arms in the O maze (P0.05 or P0.01), significantly shortened escape latency during water maze testing (P0.01 or P0.005) .LTP significantly increased the administration of the drug: AE-624. The increase of PS wave in the model group was significantly higher than that in the model group (P0.05). Compared with the normal group, the activity of SOD in serum and hippocampus of the model group was significantly decreased (P0.05). Compared with the model group, the AE-624 group significantly increased the activity of SOD in serum and hippocampus (P0.05 or P0.001), and decreased the content of MDA in serum and hippocampus (P0.05 or P0.001). Nissl staining showed that the number of neurons in the model group was significantly lower than that in the normal group (P0.01), and the number of neurons in the hippocampal area of the model group was significantly increased (P0.05) compared with the model group, which had obvious protective effect on the hippocampal neurons of the model mice. Conclusion: (1) AE-624 has obvious protective effect on PC12 cell injury induced by LPS. (2) AE-624 has obvious protective effect on cognitive function of AD model mice induced by streptozotocin (STZ), and its protective mechanism may be related to the antioxidant effect of AE-624. Anti-neuronal apoptosis and improving the synaptic plasticity of model mice by increasing LTP, in the PP-DG region of hippocampus were related.
【學(xué)位授予單位】：新疆醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R285.5;R-332

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