Wang Yan, Liu Qian, Xu Yingqiong, Zhang Yuanyuan, Lv Yanni, Tan Yisha, Jiang Nan, Cao Guosheng, Ma Xiaonan, Wang Jingrong, Cao Zhengyu, Yu Boyang, Kou Junping
State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Complex Prescription of TCM, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China.
Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210002, China.; School of Dentistry, Cardiff Institute of Tissue Engineering and Repair, Cardiff University, Heath Park, Cardiff CF14 4XY, UK.
Int J Biol Sci. 2016 Oct 25;12(11):1341-1356. doi: 10.7150/ijbs.15992. eCollection 2016.
Oxidative stress-induced cytoskeletal dysfunction of neurons has been implicated as a crucial cause of cell apoptosis or death in the central nervous system (CNS) diseases, such as neurodegenerative and psychiatric diseases. The application of neuroprotectants rescuing the neurons from cytoskeletal damage and apoptosis can be a potential treatment for these CNS diseases. Ginsenoside Rg1 (Rg1), one of the major active components of ginseng, has been reported possessing notable neuroprotective activities. However, there is rare report about its effect on cytoskeleton and its undergoing mechanism. The current study is to reveal the regulatory effects of Rg1 on cytoskeletal and morphological lesion in oxidative stress-induced neuronal apoptosis. The results demonstrated that pre-treatment with Rg1 (0.1-10 μM) attenuated hydrogen peroxide (HO)-induced neuronal apoptosis and oxidative stress through reducing the intracellular reactive oxygen species (ROS) production and methane dicarboxylic aldehyde (MDA) level. The Rg1 treatment also abolished HO-induced morphological changes, including cell rounding, membrane blebbing, neurite retraction and nuclei condensation, which were generated by myosin IIA-actin interaction. These effects were mediated via the down-regulation of caspase-3, ROCK1 (Rho-associated kinase1) activation and myosin light chain (MLC, Ser-19) phosphorylation. Furthermore, inhibiting myosin II activity with blebbistatin partly blocked the neuroprotective effects of Rg1. The computer-aided homology modelling revealed that Rg1 preferentially positioned in the actin binding cleft of myosin IIA and might block the binding of myosin IIA to actin filaments. Accordingly, the neuroprotective mechanism of Rg1 is related to the activity that inhibits myosin IIA-actin interaction and the caspase-3/ROCK1/MLC signaling pathway. These findings put some insights into the unique neuroprotective properties of Rg1 associated with the regulation of myosin IIA-actin cytoskeletal structure under oxidative stress and provide experimental evidence for Rg1 in CNS diseases.
氧化应激诱导的神经元细胞骨架功能障碍被认为是中枢神经系统（CNS）疾病（如神经退行性疾病和精神疾病）中细胞凋亡或死亡的关键原因。应用神经保护剂来挽救神经元免受细胞骨架损伤和凋亡可能是治疗这些中枢神经系统疾病的一种潜在方法。人参皂苷Rg1（Rg1）是人参的主要活性成分之一，已报道具有显著的神经保护活性。然而，关于其对细胞骨架的影响及其作用机制的报道很少。本研究旨在揭示Rg1对氧化应激诱导的神经元凋亡中细胞骨架和形态损伤的调节作用。结果表明，用Rg1（0.1 - 10 μM）预处理可通过减少细胞内活性氧（ROS）生成和丙二醛（MDA）水平来减轻过氧化氢（HO）诱导的神经元凋亡和氧化应激。Rg1处理还消除了HO诱导的形态学变化，包括细胞变圆、膜泡化、神经突回缩和核浓缩，这些变化是由肌球蛋白IIA - 肌动蛋白相互作用产生的。这些作用是通过下调半胱天冬酶 - 3、ROCK1（Rho相关激酶1）激活和肌球蛋白轻链（MLC，Ser - 19）磷酸化介导的。此外，用blebbistatin抑制肌球蛋白II活性部分阻断了Rg1的神经保护作用。计算机辅助同源建模显示，Rg1优先定位在肌球蛋白IIA的肌动蛋白结合裂隙中，并可能阻断肌球蛋白IIA与肌动蛋白丝的结合。因此，Rg1的神经保护机制与抑制肌球蛋白IIA - 肌动蛋白相互作用以及半胱天冬酶 - 3/ROCK1/MLC信号通路的活性有关。这些发现为Rg1在氧化应激下与肌球蛋白IIA - 肌动蛋白细胞骨架结构调节相关的独特神经保护特性提供了一些见解，并为Rg1在中枢神经系统疾病中的应用提供了实验证据。
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