Keap1-independent GSK-3β/Nrf2 signaling mediates electroacupuncture inhibition of oxidative stress to induce cerebral ischemia-reperfusion tolerance

IF 3.5 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2024-09-05 DOI:10.1016/j.brainresbull.2024.111071

Chunjue Ni , Baojun Huang , Yufan Huang , Zhengde Wen , Shan Luo

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Abstract

Purpose

Cerebral ischemia-reperfusion (CIR) injury is a devastating consequence of stroke characterized by oxidative stress-induced neuronal damage. Electroacupuncture (EA) has emerged as a potential therapeutic intervention for ischemic stroke, but its underlying mechanisms remain incompletely understood. This study aimed to elucidate whether EA exerts anti-oxidative stress effects against CIR injury by modulating the GSK-3β/Nrf2 pathway.

Methods

CIR mouse models were established using the suture-occluded method and underwent EA pretreatment. Cognitive and neurologic function, cerebral infarct volume, and neuronal damage were assessed in mice. Oxidative stress levels and the expression of components of the GSK-3β/Nrf2 pathway in the cerebral cortex were measured. The regulatory effect of GSK-3β on Nrf2 and its role in electroacupuncture to alleviate oxygen-glucose deprivation/reoxygenation (OGD/R)-induced neuronal injury were investigated by modulating GSK-3β expression in HT22 hippocampal neuronal cells and electroacupuncture serum intervention. Ultimately, Nrf2 knockout mice, GSK-3β knockout mice, and wild-type mice treated with TBHQ (an Nrf2 activator) were utilized for further validation.

Results

EA pretreatment improved cognitive impairment and neuronal damage induced by CIR injury. Mechanistically, EA inhibited oxidative stress in the cerebral cortex, manifested by reduced levels of reactive oxygen species and malondialdehyde, along with increased superoxide dismutase activity. Furthermore, EA upregulated the expression of Nrf2 and its downstream antioxidant enzymes HO-1 and NQO1, while Keap1 expression remained unaffected. In vitro, GSK-3β overexpression inhibited the protective effects of EA serum on OGD/R-induced neuronal damage. In vivo, knockout of either Nrf2 or Gsk-3β genes abolished the neuroprotective effects of EA, and TBHQ exerted effects similar to EA, confirming the significant role of GSK-3β/Nrf2 in mediating EA antioxidative effects.

Conclusion

EA exerts antioxidative stress effects against CIR injury by activating the GSK-3β/Nrf2 signaling pathway, independent of Keap1 regulation.

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Keap1依赖性GSK-3β/Nrf2信号介导电针抑制氧化应激以诱导脑缺血再灌注耐受性

目的：脑缺血再灌注（CIR）损伤是中风的一种破坏性后果，其特点是氧化应激诱发神经元损伤。电针（EA）已成为缺血性中风的一种潜在治疗干预手段，但其潜在机制仍不完全清楚。本研究旨在阐明 EA 是否通过调节 GSK-3β/Nrf2 通路对 CIR 损伤发挥抗氧化应激作用：方法：采用缝合-闭塞法建立 CIR 小鼠模型，并进行 EA 预处理。对小鼠的认知和神经功能、脑梗死体积和神经元损伤进行评估。测量了氧化应激水平和大脑皮层中GSK-3β/Nrf2通路成分的表达。通过调节GSK-3β在HT22海马神经元细胞中的表达和电针血清干预，研究了GSK-3β对Nrf2的调控作用及其在电针缓解氧-葡萄糖剥夺/复氧（OGD/R）诱导的神经元损伤中的作用。最终，Nrf2基因剔除小鼠、GSK-3β基因剔除小鼠和野生型小鼠经TBHQ（一种Nrf2激活剂）治疗后的结果得到进一步验证：结果：EA预处理改善了CIR损伤引起的认知障碍和神经元损伤。从机理上讲，EA抑制了大脑皮层的氧化应激，表现为活性氧和丙二醛水平的降低以及超氧化物歧化酶活性的增加。此外，EA 还能上调 Nrf2 及其下游抗氧化酶 HO-1 和 NQO1 的表达，而 Keap1 的表达则不受影响。在体外，GSK-3β的过表达抑制了EA血清对OGD/R诱导的神经元损伤的保护作用。在体内，Nrf2或Gsk-3β基因的敲除会取消EA的神经保护作用，而TBHQ的作用与EA相似，这证实了GSK-3β/Nrf2在介导EA抗氧化作用中的重要作用：结论：EA通过激活GSK-3β/Nrf2信号通路发挥抗CIR损伤的抗氧化作用，与Keap1调控无关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.