PDPOB Exerts Multiaspect Anti-Ischemic Effects Associated with the Regulation of PI3K/AKT and MAPK Signaling Pathways
PDPOB Exerts Multiaspect Anti-Ischemic Effects Associated with the Regulation of PI3K/AKT and MAPK Signaling Pathways
复制标题
PDPOB 发挥与 PI3K/AKT 和 MAPK 信号通路调节相关的多方面抗缺血作用
DOI：
10.1021/acschemneuro.1c00459
复制
发表时间：
2021
影响因子：
5
通讯作者：
Zhang Haiyan
中科院分区：
文献类型：
--
作者：
Zhao Qinyuan;Shao Xingcheng;Ding Xun;Lin Sijin;Zhang Dong;Qin Junjun;Wang Wei;Yu Weichen;Zhang Rujun;Tao Lingxue;Zhao Weimin;Zhang Haiyan
寻找新的治疗缺血性卒中的药物仍是一个迫切的需求。在这里，我们确定了一种新的苯基羧酸衍生物，正戊基4-（3，4-二羟基苯基）-4-氧代丁酸酯（PDPOB），具有抗缺血活性。采用氧糖剥夺/再灌注（OGD/R）损伤的神经细胞和脂多糖（LPS）刺激的小胶质细胞，研究PDPOB的抗缺血神经保护和抗炎作用。PDPOB可剂量依赖性地减轻OGD/R对SH-SY 5 Y细胞和原代皮层神经元的损伤。同样，PDPOB显示对OGD/R-诱发的多方面神经元退化的SH-SY 5 Y细胞的保护作用，证明了减轻线粒体功能障碍，氧化应激和凋亡。进一步的研究揭示了通过PDPO B处理的蛋白激酶B（AKT）的加速磷酸化，而磷酸肌醇3-激酶（PI 3 K）/AKT信号传导的阻断实质上降低了PDPO B的神经保护能力。此外，PDPOB预处理抑制了BV 2细胞中LPS诱发的神经炎症，其特征在于抑制了一氧化氮（NO）和促炎细胞因子的分泌，以及一氧化氮合酶（iNOS）和环氧合酶-2（考克斯-2）的正常化表达。蛋白质印迹进一步显示，PDPOB减少了过多的磷酸化的细胞外信号调节激酶（ERK），c-Jun-N-末端激酶（JNK），和p38在LPS暴露的BV 2细胞。静脉注射PDPOB（30 mg/kg，单次给药）可减轻大脑中动脉闭塞（MCAO）大鼠的同侧脑梗死，并伴有神经行为的恢复。以上结果为PDPOB调节缺血相关神经元损伤和小胶质细胞炎症提供了有力的证据和机制解释，为脑缺血治疗提供了新的思路。
The discovery of new therapeutic agents for ischemic stroke remains an urgent need. Here, we identified a novel phenyl carboxylic acid derivative,n-pentyl 4-(3,4-dihydroxyphenyl)-4-oxobutanoate (PDPOB), with anti-ischemic activities. Thein vitroanti-ischemic neuroprotective and anti-inflammatory capacities of PDPOB were investigated using neuronal cells suffering from oxygen-glucose deprivation/reperfusion (OGD/R) and microglial cells stimulated by lipopolysaccharide (LPS). PDPOB attenuated the OGD/R-evoked cellular damage of SH-SY5Y cells and primary cortical neurons in a concentration-dependent manner. Likewise, PDPOB displayed protective roles against OGD/R-evoked multiaspect neuronal deterioration in SH-SY5Y cells, as evidenced by alleviated mitochondrial dysfunction, oxidative stress, and apoptosis. A further study unveiled the accelerated phosphorylation of protein kinase B (AKT) by PDPOB treatment, while blockade of phosphoinositide 3-kinase (PI3K)/AKT signaling substantially diminished the neuroprotective capacities of PDPOB. Additionally, the PDPOB pretreatment dampened the LPS-evoked neuroinflammation in BV2 cells, characterized by the suppressed secretion of nitric oxide (NO) and proinflammatory cytokines, as well as normalized expression of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Western blotting further revealed that PDPOB abated the overabundant phosphorylation of the extracellular signal-regulated kinase (ERK), c-Jun-N-terminal kinase (JNK), and p38 in LPS-exposed BV2 cells. The intravenous application of PDPOB (30 mg/kg, single dose) attenuated ipsilateral cerebral infarction in middle cerebral artery occlusion (MCAO) rats, accompanied by recovered neurological behaviors. Collectively, the above observations provided substantial evidence for the favorable properties and mechanistic explanations of PDPOB in the regulation of ischemia-associated neuronal injury and microglial inflammation, which may furnish ideas for the discovery of new therapeutic strategies against cerebral ischemia.