Alzheimer’s disease (AD) is a severe neurodegenerative disorder of the central nervous system (CNS) characterized by neuron loss and dementia. Previous abundant evidence demonstrates that the first critical step in the course of AD is the state of oxidative stress and the neuronal loss is closely related to the interaction of several signalling pathways. The neuroprotective efficacy of Rho-associated protein kinase (ROCK) inhibitor in the treatment of AD has been reported, but its exact mechanism has not been well elucidated. The purpose of this study is to investigate the therapeutic effects of Fasudil on amyloid precursor protein/presenilin-1 (APP/PS1) mice and to discover the potential underlying mechanism. Sixteen 8-month-old APP/PS1 mice were divided into model and Fasudil treatment groups and 8 wild-type mice were used as a normal control group. After the behavioural test, all mice were sacrificed for immunofluorescence and other biochemical tests. The results showed that the administration of Fasudil improved learning and memory ability, elevated the concentration of antioxidative substances and decreased lipid peroxides, as well as inhibited neuronal apoptosis by increasing the expression of B-cell lymphoma-2 (Bcl-2) (p < 0.05), reducing Bcl-2 Associated X (Bax) (p < 0.05) and cleaved caspase-3 (p < 0.05) of APP/PS1 mice. Moreover, Fasudil treatment also ameliorated the phosphorylation of p38 (p < 0.01), c-Jun N-terminal kinase (JNK) (p < 0.001) and extracellular regulated protein kinases (ERK) (p < 0.001), and accelerated the nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) (p < 0.01) expression and its antioxidative downstream molecules (p < 0.05, p < 0.05, and p < 0.05, respectively). Data from the present study demonstrate that Fasudil significantly restored cognitive function, restrained oxidative stress and reduced neuronal apoptosis in the hippocampus, probably by inhibiting ROCK/MAPK and activating Nrf2 signalling pathways in APP/PS1 mice.

中文翻译：

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Fasudil 通过抑制 ROCK/MAPK 和激活 APP/PS1 小鼠的 Nrf2 信号通路改善认知缺陷、氧化应激和神经元凋亡

阿尔茨海默病 (AD) 是一种严重的中枢神经系统 (CNS) 神经退行性疾病，其特征是神经元丢失和痴呆。以往的大量证据表明，AD病程的第一个关键步骤是氧化应激状态，神经元丢失与多种信号通路的相互作用密切相关。Rho 相关蛋白激酶 (ROCK) 抑制剂治疗 AD 的神经保护作用已有报道，但其确切机制尚未阐明。本研究的目的是研究法舒地尔对淀粉样前体蛋白/早老素-1 (APP/PS1) 小鼠的治疗作用，并发现潜在的潜在机制。16只8月龄APP/PS1小鼠分为模型组和法舒地尔治疗组，8只野生型小鼠作为正常对照组。行为测试后，处死所有小鼠进行免疫荧光和其他生化测试。结果表明，法舒地尔通过增加B细胞淋巴瘤-2（Bcl-2）的表达，提高学习记忆能力，提高抗氧化物质浓度，降低脂质过氧化物，抑制神经元凋亡（p < 0.05)，减少 APP/PS1 小鼠的 Bcl-2 相关 X (Bax) (p < 0.05) 和裂解的 caspase-3 (p < 0.05)。此外，Fasudil 治疗还改善了 p38 (p < 0.01)、c-Jun N-末端激酶 (JNK) (p < 0.001) 和细胞外调节蛋白激酶 (ERK) (p < 0.001) 的磷酸化，并加速核因子-红细胞 2 p45 相关因子 2 (Nrf2) (p < 0.01) 表达及其抗氧化下游分子（分别为 p < 0.05、p < 0.05 和 p < 0.05）。本研究的数据表明，Fasudil 显着恢复认知功能，抑制氧化应激，减少海马神经元凋亡，可能是通过抑制 ROCK/MAPK 和激活 APP/PS1 小鼠的 Nrf2 信号通路。