新型磷酸二酯酶4抑制剂氯比普兰改善阿尔茨海默病动物认知障碍及其机制研究

发布时间：2018-03-24 07:14

本文选题：磷酸二酯酶-抑制剂　切入点：氯比普兰　出处：《中国药学杂志》2015年11期

【摘要】：目的应用海马微量注射Aβ25-35建立的大鼠学习记忆障碍模型,研究新型磷酸二酯酶4抑制剂氯比普兰对学习记忆的改善作用及机制。方法大鼠随机分为假手术组、Aβ25-35微量注射组(模型组)、氯比普兰低剂量组(0.05 mg·kg-1)、高剂量组(0.15 mg·kg-1)、咯利普兰组及多奈哌齐组。大鼠双侧海马CA1区注射10μg Aβ25-35造成认知障碍模型,24 h后给予相应的药物处理。采用水迷宫、避暗实验检测大鼠的学习记忆能力,敞箱实验测试大鼠的自主活动能力。行为学实验结束后采用蛋白质印迹法检测海马蛋白激酶A、c AMP应答元件结合蛋白磷酸化水平以及脑源性神经营养因子蛋白水平,利用实时定量聚合酶链反应分析海马组织脑源性神经营养因子mRNA水平。结果水迷宫结果显示,与模型组比较,高剂量氯比普兰、咯利普兰及多奈哌齐给药后均能显著性增加大鼠穿越平台次数及目标象限停留时间百分比。避暗实验中,模型组大鼠的逃避潜伏期显著短于假手术组,氯比普兰和多奈哌齐均能显著延长大鼠的逃避潜伏期。敞箱实验中,无论是垂直方向得分还是水平得分,各组之间均未见显著性差异;蛋白质印迹法结果表明,与模型组比较,氯比普兰低剂量、高剂量、咯利普兰和多奈哌齐组均能显著性逆转Aβ25-35引起的蛋白激酶A、c AMP应答元件结合蛋白磷酸化水平的下降,增加脑源性神经营养因子mRNA及蛋白表达水平。结论氯比普兰有显著改善阿尔迪海默病动物学习记忆障碍的作用,该效应可能与激活蛋白激酶A/c AMP应答元件结合蛋白信号通路,促进脑源性神经营养因子的表达有关。
[Abstract]:Objective to establish a rat model of learning and memory impairment by microinjection of A 尾 25-35 into hippocampus. To study the effect and mechanism of a new phosphodiesterase 4 inhibitor, clopipran, on learning and memory. Methods Rats were randomly divided into sham-operation group (model group), chlorbipran low dose group (0.05 mg 路kg ~ (-1)), high dose group (0.15 mg 路kg ~ (-1)), sham-operation group (A 尾 25-35) microinjection group (model group), chloropramide low dose group (0.05 mg 路kg ~ (-1)). The model of cognitive impairment induced by 10 渭 g A 尾 25-35 in bilateral hippocampal CA1 was treated with water maze for 24 hours. The learning and memory ability of rats was measured by dark avoidance experiment. At the end of behavioral experiment, the phosphorylation level of hippocampal protein kinase A c AMP response element binding protein and brain-derived neurotrophic factor protein were detected by Western blotting. The level of brain-derived neurotrophic factor (mRNA) in hippocampal tissue was analyzed by real-time quantitative polymerase chain reaction. Rolipram and Donepezil significantly increased the frequency of crossing the platform and the percentage of the target quadrant residence time. In the avoidance experiment, the escape latency of the model group was significantly shorter than that of the sham operation group. Clopepram and Donepezil could significantly prolong the escape latency of rats. In the open box test, there was no significant difference in both vertical and horizontal scores between the two groups, and the results of Western blotting showed that, compared with the model group, there was no significant difference between the two groups. The low dose, high dose of chloropram, Lolipram and Donepezil groups could significantly reverse the decrease of protein kinase Ac AMP response element binding protein phosphorylation induced by A 尾 25-35. Conclusion Clopepram can significantly improve the learning and memory impairment of Alzheimer's disease, which may be related to the activation of protein kinase A / c AMP response element binding protein signaling pathway. To promote the expression of brain-derived neurotrophic factor.
【作者单位】：南方医科大学药学院神经精神药理学科;
【基金】：国家自然科学基金-广东联合基金(U1032006);国家自然科学基金资助项目(81373384) 国家“新药创制”科技重大专项(2012ZX09J1211003C)
【分类号】：R965

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