Li Yuan, Chen Ling, Zheng Da, Liu Jian-Xia, Liu Chao, Qi Shao-Hua, Hu Peng-Chao, Yang Xiao-Fei, Min Jia-Wei
Key Laboratory of Cognitive Science, Laboratory of Membrane Ion Channels and Medicine, College of Biomedical Engineering, South-Central Minzu University, Wuhan, China.
Department of Systems Medicine and Bioengineering, Houston Methodist Cancer Center, Weill Cornell Medicine, Houston, TX, United States.
Front Pharmacol. 2023 Feb 9;14:1103265. doi: 10.3389/fphar.2023.1103265. eCollection 2023.
Neonatal hypoxic-ischemic encephalopathy (HIE) is considered a major cause of death and long-term neurological injury in newborns. Studies have demonstrated that oxidative stress and apoptosis play a major role in the progression of neonatal HIE. Echinocystic acid (EA), a natural plant extract, shows great antioxidant and antiapoptotic activities in various diseases. However, it has not yet been reported whether EA exerts a neuroprotective effect against neonatal HIE. Therefore, this study was undertaken to explore the neuroprotective effects and potential mechanisms of EA in neonatal HIE using and experiments. In the study, a hypoxic-ischemic brain damage (HIBD) model was established in neonatal mice, and EA was administered immediately after HIBD. Cerebral infarction, brain atrophy and long-term neurobehavioral deficits were measured. Hematoxylin and eosin (H&E), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and dihydroethidium (DHE) staining were performed, and the contents of malondialdehyde (MDA) and glutathione (GSH) were detected. In the study, an oxygen-glucose deprivation/reperfusion (OGD/R) model was employed in primary cortical neurons, and EA was introduced during OGD/R. Cell death and cellular ROS levels were determined. To illustrate the mechanism, the PI3K inhibitor LY294002 and Nrf2 inhibitor ML385 were used. The protein expression levels of p-PI3K, PI3K, p-Akt, Akt, Nrf2, NQO1, and HO-1 were measured by western blotting. The results showed that EA treatment significantly reduced cerebral infarction, attenuated neuronal injury, and improved brain atrophy and long-term neurobehavioral deficits in neonatal mice subjected to HIBD. Meanwhile, EA effectively increased the survival rate in neurons exposed to OGD/R and inhibited oxidative stress and apoptosis in both and studies. Moreover, EA activated the PI3K/Akt/Nrf2 pathway in neonatal mice following HIBD and in neurons after OGD/R. In conclusion, these results suggested that EA alleviated HIBD by ameliorating oxidative stress and apoptosis activation of the PI3K/Akt/Nrf2 signaling pathway.
新生儿缺氧缺血性脑病（HIE）被认为是新生儿死亡和长期神经损伤的主要原因。研究表明，氧化应激和细胞凋亡在新生儿HIE的进展中起主要作用。紫球藻酸（EA）是一种天然植物提取物，在各种疾病中显示出强大的抗氧化和抗凋亡活性。然而，EA对新生儿HIE是否具有神经保护作用尚未见报道。因此，本研究采用体内和体外实验，探讨EA对新生儿HIE的神经保护作用及其潜在机制。在体内研究中，在新生小鼠中建立缺氧缺血性脑损伤（HIBD）模型，并在HIBD后立即给予EA。测量脑梗死、脑萎缩和长期神经行为缺陷。进行苏木精-伊红（H&E）、末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）和二氢乙锭（DHE）染色，并检测丙二醛（MDA）和谷胱甘肽（GSH）的含量。在体外研究中，在原代皮层神经元中采用氧糖剥夺/再灌注（OGD/R）模型，并在OGD/R期间加入EA。测定细胞死亡和细胞活性氧水平。为阐明其机制，使用了PI3K抑制剂LY294002和Nrf2抑制剂ML385。通过蛋白质印迹法测定p-PI3K、PI3K、p-Akt、Akt、Nrf2、NQO1和HO-1的蛋白表达水平。结果表明，EA治疗显著减少了HIBD新生小鼠的脑梗死，减轻了神经元损伤，改善了脑萎缩和长期神经行为缺陷。同时，在体内和体外研究中，EA均有效提高了OGD/R处理神经元的存活率，并抑制了氧化应激和细胞凋亡。此外，EA激活了HIBD新生小鼠和OGD/R后神经元中的PI3K/Akt/Nrf2通路。总之，这些结果表明，EA通过改善氧化应激和细胞凋亡以及激活PI3K/Akt/Nrf2信号通路减轻了HIBD。
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