美金刚/瑞舒伐他汀治疗消除阿尔茨海默病大鼠实验模型的认知和海马损伤:TGF-β1/Smad信号通路和淀粉样蛋白-β清除的作用

Esraa F Zidan, Nesrine S El-Mezayen, Safaa H Elrewini, Elham A Afify, Mennatallah A Ali
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引用次数: 0

摘要

阿尔茨海默病(AD)是一种多因素神经退行性疾病,具有复杂的发病机制和多种相互作用的信号通路,其中淀粉样β蛋白(a β)清除在认知能力下降中起着至关重要的作用。本研究探讨美金刚/瑞舒伐他汀治疗对TGF-β1/p-Smad/p21信号通路的可能调节作用及其与a -β -清除相关血脑屏障转运蛋白和microrna的相关性,作为AD治疗的一种新的分子机制。采用单次脑室内注射链脲佐菌素(ICV-STZ, 3 mg/kg)诱导大鼠AD,诱导后持续用药28 d。通过应用一系列行为评估以及生化、组织病理学、分子和基因表达技术来监测疗效。未经治疗的大鼠TGF-β1信号的上调与调节a -β外排的转运蛋白和microrna高度相关;表达ABCA1/miRNA-26和LRP1/miRNA-205,而不是RAGE/miRNA-185控制a - β内流;这一效应被测试药物所反对,并且被发现也与TGF-β1信号的消失有关。美刚/瑞舒伐他汀联合治疗改善了STZ诱发的Morris水迷宫逃避潜伏期和交叉次数、y迷宫自发交替率、物体识别辨别和识别指标的降低。诱发的行为反应与β-淀粉样蛋白的积累及其清除的改变直接相关。此外,药物治疗增加脑谷胱甘肽和降低丙二醛水平。这些发现被AD大鼠海马CA1区胶质细胞增生的显著减少和神经元完整性的恢复所证实。这些发现提示,美金刚/瑞舒伐他汀联合治疗可通过阻断TGF-β1/p-Smad2/p21通路,调节a -β清除,为AD治疗提供新的治疗潜力。
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Memantine/Rosuvastatin Therapy Abrogates Cognitive and Hippocampal Injury in an Experimental Model of Alzheimer's Disease in Rats: Role of TGF-β1/Smad Signaling Pathway and Amyloid-β Clearance.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder of complex pathogenesis and multiple interacting signaling pathways where amyloidal-β protein (Aβ) clearance plays a crucial role in cognitive decline. Herein, the current study investigated the possible modulatory effects of memantine/ rosuvastatin therapy on TGF-β1/p-Smad/p21 signaling pathway and their correlation to the blood brain barrier transporters involved in Aβ-clearance and microRNAs as a novel molecular mechanism in AD treatment. AD was induced by a single intracerebroventricular streptozotocin injection (ICV-STZ, 3 mg/kg) in rats and drug therapy was continued for 28 days after AD induction. Efficacy was monitored by applying a battery of behavioral assessments, as well as biochemical, histopathological, molecular and gene expression techniques. The upregulated TGF-β1-signaling in the untreated rats was found to be highly correlated to transporters and microRNAs governing Aβ-efflux; ABCA1/miRNA-26 and LRP1/miRNA-205 expressions, rather than RAGE/miRNA-185 controlling Aβ-influx; an effect that was opposed by the tested drugs and was found to be correlated with the abolished TGF-β1-signaling as well. Combined memantine/rosuvastatin therapy ameliorated the STZ evoked decreases in escape latency and number of crossovers in the Morris water maze test, % spontaneous alternation in the Y-maze test, and discrimination and recognition indices in the object recognition test. The evoked behavioral responses were directly related to the β-amyloid accumulation and the alteration in its clearance. Additionally, drug treatment increased brain glutathione and decreased malondialdehyde levels. These findings were histopathologically confirmed by a marked reduction of gliosis and restoration of neuronal integrity in the CA1 region of the hippocampus of the AD rats. These findings implicated that the memantine/rosuvastatin combination could offer a new therapeutic potential for AD management by abrogating the TGF-β1/p-Smad2/p21 pathway and regulating Aβ-clearance.

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