Inhibition of PDE4 protects neurons against oxygen-glucose deprivation-induced endoplasmic reticulum stress through activation of the Nrf-2/HO-1 pathway
Inhibition of PDE4 protects neurons against oxygen-glucose deprivation-induced endoplasmic reticulum stress through activation of the Nrf-2/HO-1 pathway
复制标题
抑制 PDE4 通过激活 Nrf-2/HO-1 通路保护神经元免受氧葡萄糖剥夺诱导的内质网应激
DOI：
10.1016/j.redox.2019.101342
复制
发表时间：
2019-10
期刊：
影响因子：
11.4
通讯作者：
Wang Haitao
中科院分区：
文献类型：
--
作者：
Xu Bingtian;Qin Yunyun;Li Dan;Cai Ningbo;Wu Jinling;Jiang Lan;Jie Limei;Zhou Zhongzhen;Xu Jiangping;Wang Haitao
抑制磷酸二酯酶4（PDE 4）对脑缺血产生神经保护作用。然而，涉及的机制仍不清楚。内质网（ER）应激的增强促进神经元凋亡，而过度的氧化应激是ER应激的诱导剂。本研究旨在确定抑制ER应激是否参与PDE 4抑制对脑缺血的保护作用。我们发现HT-22细胞暴露于氧-葡萄糖剥夺（OGD）显著激活了ER应激，表现为78-kDa葡萄糖调节蛋白（GRP 78）、磷酸化真核细胞增殖起始因子2α（eIF 2 α）和C/EBP同源蛋白（CHOP）的表达增加。在HT-22细胞中，PDE 4 B的过表达增加了ER应激，而敲低PDE 4 B或用PDE 4抑制剂FCPR 03处理可防止OGD诱导的ER应激。此外，FCPR 03促进核因子红细胞2相关因子2（Nrf-2）从细胞质易位到细胞核。重要的是，Nrf-2抑制剂ML 385阻断了FCPR 03对OGD诱导的ER应激的抑制作用。ML 385还消除了FCPR 03在经受OGD的HT-22细胞中的保护作用。敲低血红素加氧酶-1（HO-1）（其是Nrf-2的靶点）也阻断了FCPR 03的保护作用，提高了活性氧（ROS）的水平，并增加了ER应激和细胞死亡。然后我们发现FCPR 03或抗氧化剂N-乙酰基-L-半胱氨酸可以降低暴露于OGD的细胞的氧化应激。这种作用伴随着细胞活力的增加和ER应激的降低。在原代培养的神经元中，我们发现FCPR 03减少OGD诱导的ROS产生和eIF 2 α的磷酸化。FCPR 03对神经元中OGD的神经保护作用被ML 385阻断。这些结果表明，PDE 4的抑制激活Nrf-2/HO-1，减弱ROS的产生，从而减弱暴露于OGD的神经元中的ER应激。此外，我们的结论是，FCPR 03可能代表一个有前途的治疗剂，用于治疗ER应激相关疾病。
Inhibition of phosphodiesterase 4 (PDE4) produces neuroprotective effects against cerebral ischemia. However, the involved mechanism remains unclear. Augmentation of endoplasmic reticulum (ER) stress promotes neuronal apoptosis, and excessive oxidative stress is an inducer of ER stress. The present study aimed to determine whether suppression of ER stress is involved in the protective effects of PDE4 inhibition against cerebral ischemia. We found that exposing HT-22 cells to oxygen-glucose deprivation (OGD) significantly activated ER stress, as evidenced by increased expression of the 78-kDa glucose-regulated protein (GRP78), phosphorylated eukaryotic translation-initiation factor 2α (eIF2α), and C/EBP-homologous protein (CHOP). Overexpression of PDE4B increased ER stress, while knocking down PDE4B or treatment with the PDE4 inhibitor, FCPR03, prevented OGD-induced ER stress in HT-22 cells. Furthermore, FCPR03 promoted the translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm to the nucleus. Importantly, the Nrf-2 inhibitor, ML385, blocked the inhibitory role of FCPR03 on OGD-induced ER stress. ML385 also abolished the protective role of FCPR03 in HT-22 cells subjected to OGD. Knocking down heme oxygenase-1 (HO-1), which is a target of Nrf-2, also blocked the protective role of FCPR03, enhanced the level of reactive oxygen species (ROS), and increased ER stress and cell death. We then found that FCPR03 or the antioxidant, N-Acetyl-l-cysteine, reduced oxidative stress in cells exposed to OGD. This effect was accompanied by increased cell viability and decreased ER stress. In primary cultured neurons, we found that FCPR03 reduced OGD-induced production of ROS and phosphorylation of eIF2α. The neuroprotective effect of FCPR03 against OGD in neurons was blocked by ML385. These results demonstrate that inhibition of PDE4 activates Nrf-2/HO-1, attenuates the production of ROS, and thereby attenuates ER stress in neurons exposed to OGD. Additionally, we conclude that FCPR03 may represent a promising therapeutic agent for the treatment of ER stress-related disorders.
登录
查看更多内容
影响因子：
29
作者：
Yaghi S;Boehme AK;Dibu J;Leon Guerrero CR;Ali S;Martin-Schild S;Sands KA;Noorian AR;Blum CA;Chaudhary S;Schwamm LH;Liebeskind DS;Marshall RS;Willey JZ
通讯作者：
Willey JZ
影响因子：
5.6
作者：
Li, Yueyong;Zhang, Yingjun;Liao, Pinhu
通讯作者：
Liao, Pinhu
影响因子：
21.3
作者：
通讯作者：
--
Apelin 13 通过激活 AMPK/GSK-3β/Nrf2 信号对缺血性中风的神经保护作用
影响因子：
9.3
作者：
Duan, Jialin;Cui, Jia;Wen, Aidong
通讯作者：
Wen, Aidong
影响因子：
5
作者：
Zhong-Zhen Zhou;Yufang Cheng;Zhengqiang Zou;Bing-Chen Ge;Hui Yu;Cang Huang;Hai-Tao Wang;Xue-Mei Yang;Jiangping Xu
通讯作者：
Zhong-Zhen Zhou;Yufang Cheng;Zhengqiang Zou;Bing-Chen Ge;Hui Yu;Cang Huang;Hai-Tao Wang;Xue-Mei Yang;Jiangping Xu