Gartanin Protects Neurons against Glutamate-Induced Cell Death in HT22 Cells: Independence of Nrf-2 but Involvement of HO-1 and AMPK
Gartanin Protects Neurons against Glutamate-Induced Cell Death in HT22 Cells: Independence of Nrf-2 but Involvement of HO-1 and AMPK
复制标题
Gartanin 保护神经元免受 HT22 细胞中谷氨酸诱导的细胞死亡：Nrf-2 的独立性，但 HO-1 和 AMPK 的参与
DOI：
10.1007/s11064-016-1941-x
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发表时间：
2016-09-01
影响因子：
4.4
通讯作者：
Yang, Xiao-bo
中科院分区：
文献类型：
--
作者：
Gao, Xiao-yun;Wang, Sheng-nan;Yang, Xiao-bo
氧化应激介导神经退行性疾病的发病机制。山竹皂苷是山竹中的一种天然氧杂蒽酮，具有多种药理活性。本文首次研究了gartanin对谷氨酸诱导的HT 22细胞损伤的神经保护作用及其可能的机制。谷氨酸以剂量依赖性方式导致细胞死亡，补充1-10 µM gartanin可防止谷氨酸对细胞存活的不利影响。对潜在机制的进一步研究表明，gartanin可以有效地减少谷氨酸诱导的细胞内ROS产生和线粒体去极化。我们进一步发现，gartanin诱导HO-1的表达独立于核因子红细胞衍生2-样2（Nrf 2）。随后的研究表明，gartanin对谷氨酸诱导的细胞凋亡的抑制作用被小干扰RNA介导的HO-1敲低部分阻断。最后，经gartanin处理后，AMP活化蛋白激酶（AMPK）及其下游信号分子Sirtuin activator（SIRT 1）和过氧化物酶体增殖物活化受体-γ共激活因子-1 α（PGC-1α）的磷酸化蛋白表达增加。综上所述，这些结果表明，gartanin是一种潜在的神经保护剂，部分通过增加Nrf-2-独立的HO-1和AMPK/SIRT 1/PGC-1α信号通路来对抗谷氨酸诱导的氧化损伤。
Oxidative stress mediates the pathogenesis of neurodegenerative disorders. Gartanin, a natural xanthone of mangosteen, possesses multipharmacological activities. Herein, the neuroprotection capacity of gartanin against glutamate-induced damage in HT22 cells and its possible mechanism(s) were investigated for the first time. Glutamate resulted in cell death in a dose-dependent manner and supplementation of 1–10 µM gartanin prevented the detrimental effects of glutamate on cell survival. Additional investigations on the underlying mechanisms suggested that gartanin could effectively reduce glutamate-induced intracellular ROS generation and mitochondrial depolarization. We further found that gartanin induced HO-1 expression independent of nuclear factor erythroid-derived 2-like 2 (Nrf2). Subsequent studies revealed that the inhibitory effects of gartanin on glutamate-induced apoptosis were partially blocked by small interfering RNA-mediated knockdown of HO-1. Finally, the protein expression of phosphorylation of AMP-activated protein kinase (AMPK) and its downstream signal molecules, Sirtuin activator (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), increased after gartanin treatment. Taken together, these findings suggest gartanin is a potential neuroprotective agent against glutamate-induced oxidative injury partially through increasing Nrf-2-independed HO-1 and AMPK/SIRT1/PGC-1α signaling pathways.