Li Li, Yang Na, Nin Ling, Zhao Zhilong, Chen Lu, Yu Jie, Jiang Zhuyun, Zhong Zhendong, Zeng Daiwen, Qi Hongyi, Xu Xiaoyu
College of Pharmaceutical Sciences, Southwest University, 2 Tiansheng Road, Beibei District, Chongqing, 400716, People's Republic of China.
J Nat Med. 2015 Jan;69(1):76-85. doi: 10.1007/s11418-014-0865-5. Epub 2014 Aug 23.
The Chinese herbal medicine formula Tao Hong Si Wu decoction (THSWD) is traditionally used for the prevention and treatment of ischemic stroke. Transcription factor NF-E2-related factor 2 (Nrf2) regulates a battery of phase II enzymes and is known as the major mechanism of cellular defense against oxidative stress. The present study aimed to explore the potential effect of THSWD on the Nrf2 signaling pathway and the consequent effect during cerebral ischemia-reperfusion (I/R) injury. We found that THSWD reduced infarct volume and improved neurological function in a rat stroke model induced by middle cerebral artery occlusion (MCAO). Additionally, heme oxygenase 1 (HO-1), a key endogenous antioxidant enzyme regulated by Nrf2, was significantly further induced by THSWD in this in vivo model. In neuronal-like PC12 cells, THSWD remarkably up-regulated HO-1 expression and promoted Nrf2 nuclear translocation. Furthermore, phosphatidylinositol 3-kinase (PI3K)/Akt kinase was found to be involved in the upstream of Nrf2 regulation. In an in vitro oxygen-glucose deprivation/reperfusion (OGD-Rep) model, THSWD treatment significantly reduced cell death induced by OGD-Rep insult. Importantly, the protective action was attenuated while PI3K activity was inhibited by a specific inhibitor, LY294002, and the Nrf2 signaling pathway was blocked by antioxidant response element (ARE) decoy oligonucleotides. Collectively, these results demonstrated that THSWD exhibited notable neuroprotective properties in vitro and in vivo and activation of PI3K/Akt and the Nrf2 signaling pathway may be, at least in part, responsible for the protection. This study provides a better understanding of the molecular mechanism underlying the traditional use of the Chinese herbal medicine formula THSWD.
中药方剂桃红四物汤（THSWD）传统上用于预防和治疗缺血性中风。转录因子NF-E2相关因子2（Nrf2）调节一系列II期酶，是细胞抵御氧化应激的主要机制。本研究旨在探讨THSWD对Nrf2信号通路的潜在影响以及在脑缺血再灌注（I/R）损伤中的后续作用。我们发现，在大脑中动脉闭塞（MCAO）诱导的大鼠中风模型中，THSWD减少了梗死体积并改善了神经功能。此外，血红素加氧酶1（HO-1）是一种由Nrf2调节的关键内源性抗氧化酶，在该体内模型中，THSWD显著进一步诱导了其表达。在神经元样PC12细胞中，THSWD显著上调HO-1表达并促进Nrf2核转位。此外，发现磷脂酰肌醇3激酶（PI3K）/Akt激酶参与Nrf2调节的上游过程。在体外氧糖剥夺/再灌注（OGD-Rep）模型中，THSWD处理显著减少了OGD-Rep损伤诱导的细胞死亡。重要的是，当PI3K活性被特异性抑制剂LY294002抑制且Nrf2信号通路被抗氧化反应元件（ARE）诱饵寡核苷酸阻断时，保护作用减弱。总体而言，这些结果表明，THSWD在体外和体内均表现出显著的神经保护特性，PI3K/Akt和Nrf2信号通路的激活可能至少部分地负责这种保护作用。本研究为更好地理解中药方剂THSWD传统用途的分子机制提供了依据。
