Inhibition of PDE4 by FCPR16 induces AMPK-dependent autophagy and confers neuroprotection in SH-SY5Y cells and neurons exposed to MPP -induced oxidative insult
Inhibition of PDE4 by FCPR16 induces AMPK-dependent autophagy and confers neuroprotection in SH-SY5Y cells and neurons exposed to MPP -induced oxidative insult
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FCPR16 抑制 PDE4 可诱导 AMPK 依赖性自噬，并为暴露于 MPP 诱导的氧化损伤的 SH-SY5Y 细胞和神经元提供神经保护
DOI：
10.1016/j.freeradbiomed.2019.02.027
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发表时间：
2019
影响因子：
7.4
通讯作者：
Wang Haitao
中科院分区：
文献类型：
--
作者：
Zhong Jiahong;Xie Jinfeng;Xiao Jiao;Li Dan;Xu Bingtian;Wang Xinyi;Wen Huizhen;Zhou Zhongzhen;Cheng Yufang;Xu Jiangping;Wang Haitao
帕金森氏病（PD）的病因通常还不清楚，但据信涉及过度氧化损伤。因此，鉴定对氧化损伤表现出保护作用的治疗靶点和化合物是减缓PD进展的合理策略。FCPR 16是一种新型的磷酸二酯酶4抑制剂，几乎没有催吐潜力。我们的前期研究表明FCPR 16能够阻断1-甲基-4-苯基吡啶（MPP+）诱导的SH-SY 5 Y细胞和神经元的氧化损伤。然而，其详细机制尚不清楚。在这里，我们发现FCPR 16触发了SH-SY 5 Y细胞中的自噬，如微管相关蛋白1轻链3 II（LC 3-II）水平增加和p62降低所证明的。用3-MA或氯喹抑制自噬可降低FCPR 16对自噬空泡积聚和溶酶体荧光信号的影响。在MPP+处理的SH-SY 5 Y细胞中，我们发现FCPR 16增加了LC 3-II的水平，3-MA减弱了FCPR 16对MPP+诱导的毒性的保护作用。用FCPR 16处理SH-SY 5 Y细胞可防止MPP+诱导的活性氧（ROS）产生和线粒体膜电位（Δ Km）下降。重要的是，我们还发现FCPR 16磷酸化并因此激活MPP+处理的SH-SY 5 Y细胞中的AMP活化蛋白激酶（AMPK）。相反，用化合物C阻断AMPK途径阻断了FCPR 16在自噬增强中的作用。同样，化合物C也阻断了FCPR 16在产生ROS、降低Δ λ m和神经保护中的作用。在原代培养的神经元中一致地获得了类似的结果。总之，这些结果表明FCPR 16通过AMPK依赖性自噬有效保护SH-SY 5 Y细胞和神经元免受氧化应激。我们的研究结果表明FCPR 16在PD治疗中的潜在应用。
The etiology of Parkinson's disease (PD) is generally not well understood, but it is believed to involve excessive oxidative insult. Hence, identifying therapeutic targets and compounds that exhibit protective effects against oxidative damage is a reasonable strategy to slow down the progression of PD. FCPR16 is a novel phosphodiesterase 4 inhibitor with little emetic potential. Our previous studies showed that FCPR16 was able to block 1-Methyl-4-phenylpyridine (MPP+)-induced oxidative damage in SH-SY5Y cells and neurons. However, the detailed mechanism of this is unknown. Here, we found that FCPR16 triggered autophagy in SH-SY5Y cells, as evidenced by an increased level of microtubule-associated protein 1 light chain 3 II (LC3-II) and decreased p62. Inhibition of autophagy by 3-MA or chloroquine decreased the effect of FCPR16 on the accumulation of autophagic vacuoles and the fluorescence signal of lysosomes. In SH-SY5Y cells treated with MPP+, we found that FCPR16 increased the level of LC3-II, and 3-MA attenuated the protective effect of FCPR16 against MPP+-induced toxicity. Treatment of SH-SY5Y cells with FCPR16 prevented MPP+-induced production of reactive oxygen species (ROS) and the decline of mitochondrial membrane potential (Δψm). Importantly, we also found that FCPR16 phosphorylated and thus activated AMP-activated protein kinase (AMPK) in SH-SY5Y cells treated with MPP+. In contrast, blockade of the AMPK pathway with compound C blocked the role of FCPR16 in autophagy enhancement. Similarly, the roles of FCPR16 in the production of ROS, decline of Δψm, and neuroprotection were blocked by compound C as well. Similar results were consistently obtained in primary cultured neurons. Taken together, these results suggest that FCPR16 is effective in protecting SH-SY5Y cells and neurons against oxidative stress via AMPK-dependent autophagy. Our findings indicate the potential application of FCPR16 in PD treatment.