Genistein attenuates ischemic oxidative damage and behavioral deficits via eNOS/Nrf2/HO-1 signaling
Genistein attenuates ischemic oxidative damage and behavioral deficits via eNOS/Nrf2/HO-1 signaling
复制标题
金雀异黄素通过 eNOS/Nrf2/HO-1 信号传导减轻缺血性氧化损伤和行为缺陷
DOI：
10.1002/hipo.22126
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发表时间：
2013-07-01
期刊：
影响因子：
3.5
通讯作者：
Yang, Fang
中科院分区：
文献类型：
--
作者：
Wang, Ruimin;Tu, Jingyi;Yang, Fang
全脑缺血，例如心脏骤停后发生的缺血，可导致氧化应激、海马神经元细胞死亡和认知缺陷。目前的研究探讨了天然异黄酮植物雌激素金雀异黄酮治疗后的潜在有益作用和潜在机制，金雀异黄素与减轻氧化应激有关。静脉注射金雀异黄酮 (1 mgkg-1)。遭受四血管全脑缺血 (GCI) 的大鼠再灌注后 5 分钟。结果表明，GCI 后金雀异黄素对海马 CA1 神经元具有显着的神经保护作用，NeuN 阳性神经元的增加和 TUNEL 阳性神经元的减少就证明了这一点。此外，与载体对照动物相比，金雀异黄素治疗还显着改善了空间学习和记忆。金雀异黄素的有益作用似乎是通过 eNOS 磷酸化/激活的增加以及随后抗氧化/解毒 Nrf2/Keap1 转录系统的激活来介导的。沿着这些思路，金雀异黄素增加了 keap1 S-亚硝基化，相应地在核中积累并增强了 Nrf2 的 DNA 结合活性。与载体对照组相比，金雀异黄素还提高了 Nrf2 下游抗氧化蛋白、血红素加氧酶 (HO)-1 的水平。通过对氧化应激标记物 8-羟基-2-脱氧鸟苷 (8-OHdG) 和 4-羟基壬烯醛进行免疫荧光染色测量，金雀异黄素可诱导 Nrf2 激活，从而显着减弱 GCI 后海马 CA1 神经元的氧化 DNA 损伤和脂质过氧化损伤。 (4-HNE)。有趣的是，用 L-NAME（一种 eNOS 激活抑制剂）预处理可以消除金雀异黄素的上述作用。总之，研究结果表明，低剂量金雀异黄素可以在 GCI 后的海马 CA1 区发挥显着的抗氧化、神经保护和认知增强作用。从机制上讲，金雀异黄素的有益作用似乎是通过增强 eNOS 磷酸化/激活和一氧化氮 (NO) 介导的 Keap1 硫醇修饰来介导的，随后上调 Nrf2/HO-1 抗氧化信号通路，从而减弱氧化应激。 (c) 2013 年 Wiley 期刊公司。
Global cerebral ischemia, such as occurs following cardiac arrest, can lead to oxidative stress, hippocampal neuronal cell death, and cognitive defects. The current study examined the potential beneficial effect and underlying mechanisms of post-treatment with the naturally occurring isoflavonic phytoestrogen, genistein, which has been implicated to attenuate oxidative stress. Genistein (1 mgkg-1) was administered i.v. 5 min after reperfusion in rats subjected to four-vessel global cerebral ischemia (GCI). The results revealed that genistein exerted significant neuroprotection of hippocampal CA1 neurons following GCI, as evidenced by an increase in NeuN-positive neurons and the decrease in TUNEL-positive neurons. Furthermore, genistein treatment also resulted in significantly improved spatial learning and memory as compared to vehicle control animals. The beneficial effects of genistein appear to be mediated by an increase of phosphorylation/activation of eNOS, with subsequent activation of the antioxidant/detoxification Nrf2/Keap1 transcription system. Along these lines, genistein increased keap1 S-nitrosylation, with a corresponding nuclear accumulation and enhanced DNA binding activity of Nrf2. Genistein also enhanced levels of the Nrf2 downstream antioxidant protein, heme oxygenase (HO)-1, as compared to vehicle control groups. In accordance with its induction of Nrf2 activation, genistein exerted a robust attenuation of oxidative DNA damage and lipid peroxidative damage in hippocampal CA1 neurons after GCI, as measured by immunofluorescence staining of the oxidative stress markers, 8-hydroxy-2-deoxyguanosine (8-OHdG) and 4-Hydroxynonenal (4-HNE). Interestingly, the aforementioned effects of genistein were abolished by pretreatment with L-NAME, an inhibitor of eNOS activation. In conclusion, the results of the study demonstrate that low dose genistein can exert significant antioxidant, neuroprotective, and cognitive-enhancing effects in the hippocampal CA1 region following GCI. Mechanistically, the beneficial effects of genistein appear to be mediated by enhanced eNOS phosphorylation/activation and nitric oxide (NO)-mediated thiol modification of Keap1, with subsequent upregulation of the Nrf2/HO-1 antioxidative signaling pathway and a resultant attenuation of oxidative stress. (c) 2013 Wiley Periodicals, Inc.