新型PDE4抑制剂Roflupram改善阿尔茨海默病大鼠的认知障碍及神经炎症

发布时间：2018-01-30 21:07

本文关键词： Roflupram 阿尔茨海默病 PDE抑制剂神经炎症 β-淀粉样蛋白认知小胶质细胞　出处：《中国药理学通报》2015年03期 　论文类型：期刊论文

【摘要】：目的验证新型PDE4抑制剂罗氟普兰(roflupram)能否改善Aβ25-35诱导的阿尔茨海默病大鼠的学习记忆障碍,及可能的机制是否与缓解小胶质细胞激活引起的炎症相关。方法 SD大鼠双侧海马CA1区微量注射Aβ25-35(10μg)造模。动物分组包括:假手术对照组、Aβ25-35注射组、Aβ25-35注射+盐酸多奈哌齐组、Aβ25-35注射+Rolipram组、Aβ25-35注射+Roflupram低、中、高剂量。连续灌胃给药14 d后,进行Morris水迷宫实验,20 d后进行避暗实验。采用Western blot法检测海马c AMP下游信号分子(p-PKA、p-CREB),前致炎因子(i NOS、COX-2、TNF-α、IL-1β),胶质细胞激活标记物(GFAP、Iba-1),炎症相关蛋白(p-p38、核内NF-κB p65)的蛋白水平变化,并用PCR的方法分析海马内i NOS、COX-2、TNF-α和IL-1βmRNA水平的变化。结果行为学结果显示,Roflupram能明显改善由Aβ25-35造成大鼠的空间学习记忆能力和被动回避学习记忆能力障碍。分子生物学分析的结果如下:与Aβ25-35注射组比较,各药物处理后均可以使海马内p-CREB、p-PKA蛋白表达水平不同程度的升高,使NF-κB p65(核内)、p-p38、i NOS、COX-2、TNF-α、IL-1β、GFAP和Iba-1的蛋白水平不同程度的降低,i NOS、COX-2、TNF-α和IL-1βmRNA水平下降。结论 Roflupram能够改善Aβ25-35诱导痴呆大鼠的学习记忆功能障碍,该效应与抑制小胶质细胞的活化、减少炎性因子的表达,从而缓解神经炎症有关。
[Abstract]:Objective to investigate whether rofluprama, a new PDE4 inhibitor, can improve learning and memory impairment induced by A 尾 25-35 in rats with Alzheimer's disease. Methods microinjection of A 尾 25-35 10 渭 g into bilateral hippocampal CA1 region of SD rats was carried out in order to alleviate inflammation induced by microglial activation. The animals were divided into three groups: sham operation control group. The A 尾 25-35 injection group (A 尾 25-35) injected with Donepezil hydrochloride group (A 尾 25-35) injected with Rolipram group (A 尾 25-35) group was low in Roflupram. The Morris water labyrinth test was carried out after 14 days of intragastric administration. After 20 days, the Western blot method was used to detect the downstream signal molecule of c AMP in hippocampus, p-PKAn p-CREBN, and proinflammatory factor I NOS. COX-2TNF- 伪 -IL-1 尾, glial activation marker GFAPA-1, inflammatory related protein p-p38. The protein level of NF- 魏 B p65) was determined by PCR. Changes of TNF- 伪 and IL-1 尾 mRNA levels. Roflupram could significantly improve the spatial learning and memory ability and the ability of passive avoidance learning and memory in rats caused by A 尾 25-35. The results of molecular biology analysis were as follows:. Compared with A 尾 25-35 injection group. After treatment with various drugs, the expression of p-CREBN p-PKA protein in hippocampus was increased to varying degrees, and NF- 魏 B p65 (p-p38 NOS) was induced. The protein levels of GFAP and Iba-1 in TNF- 伪 TNF- 伪 and Iba-1 decreased in varying degrees. Conclusion Roflupram can improve the learning and memory function of dementia rats induced by A 尾 25-35. This effect is related to inhibiting the activation of microglia and reducing the expression of inflammatory factors.
【作者单位】：南方医科大学药学院药理学系;
【基金】：国家自然科学基金委员会-广东省人民政府联合基金资助项目(No U1032006) 国家自然科学基金资助项目(No81373384)
【分类号】：R965
【正文快照】： 阿尔茨海默病(Alzheimer’s disease,AD)是一种以渐进性记忆减退、认知障碍及人格改变为主要临床特征的中枢神经系统退行性变性疾病。脑内老年斑(senile plaques,SPs)形成、含有tau蛋白的神经纤维缠结(neurofibrillary tangles,NTFs)以及神经元缺失变性是其三大病理学特征[1]

【相似文献】