Department of Joint Surgery, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China.
Department of Anesthesiology, The Second Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine, Xianyang, 712000, Shaanxi, China.
Cell Mol Neurobiol. 2021 Mar;41(2):377-393. doi: 10.1007/s10571-020-01009-8. Epub 2020 Nov 19.
Abnormal excessive production and deposition of β-amyloid (Aβ) peptides in selectively susceptible brain regions are thought to be a key pathogenic mechanism underlying Alzheimer's disease (AD), resulting in memory deficits and cognitive impairment. Genistein is a phytoestrogen with great promise for counteracting diverse Aβ-induced insults, including oxidative stress and mitochondrial dysfunction. However, the exact molecular mechanism or mechanisms underlying the neuroprotective effects of genistein against Aβ-induced insults are largely uncharacterized. To further elucidate the possible mechanism(s) underlying these protective effects, we investigated the neuroprotective effects of genistein against Aβ-induced oxidative stress mediated by orchestrating α7 nicotinic acetylcholine receptor (α7nAChR) signaling in rat primary hippocampal neurons. Genistein significantly increased cell viability, reduced the number of apoptotic cells, decreased accumulation of reactive oxygen species (ROS), decreased contents of malondialdehyde (MDA) and lactate dehydrogenase (LDH), upregulated BCL-2 expression, and suppressed Caspase-3 activity occurring after treatment with 25 μM Aβ25-35. Simultaneously, genistein markedly inhibited the decreases in α7nAChR mRNA and protein expression in cells treated with Aβ25-35. In addition, α7nAChR signaling was intimately involved in the genistein-mediated activation of phosphatidylinositol 3-kinase (PI3K)/Akt and Nrf2/keap1 signaling. Thus, α7nAChR activity together with the PI3K/Akt/Nrf2 signaling cascade likely orchestrates the molecular mechanism underlying the neuroprotective effects of genistein against Aβ-induced oxidative injury.
β-淀粉样蛋白（Aβ）肽的异常过度产生和沉积被认为是阿尔茨海默病（AD）的关键致病机制，导致记忆缺陷和认知障碍。染料木黄酮是一种植物雌激素，具有对抗多种 Aβ 诱导损伤的巨大潜力，包括氧化应激和线粒体功能障碍。然而，染料木黄酮对 Aβ 诱导损伤的神经保护作用的确切分子机制或机制在很大程度上尚未确定。为了进一步阐明这些保护作用的可能机制，我们研究了染料木黄酮对 Aβ 诱导的氧化应激的神经保护作用，该作用通过协调大鼠原代海马神经元中 α7 烟碱型乙酰胆碱受体（α7nAChR）信号来实现。染料木黄酮显著增加细胞活力，减少凋亡细胞数量，减少活性氧（ROS）的积累，降低丙二醛（MDA）和乳酸脱氢酶（LDH）的含量，上调 BCL-2 表达，并抑制 Aβ25-35 处理后 Caspase-3 活性的发生。同时，染料木黄酮明显抑制 Aβ25-35 处理细胞中 α7nAChR mRNA 和蛋白表达的降低。此外，α7nAChR 信号通路与染料木黄酮介导的磷酸肌醇 3-激酶（PI3K）/Akt 和 Nrf2/keap1 信号通路的激活密切相关。因此，α7nAChR 活性以及 PI3K/Akt/Nrf2 信号级联可能协调了染料木黄酮对 Aβ 诱导的氧化损伤的神经保护作用的分子机制。
