Transcranial direct current stimulation enhances the protective effect of isoflurane preconditioning on cerebral ischemia/reperfusion injury: A new mechanism associated with the nuclear protein Akirin2

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2024-09-12 DOI:10.1111/cns.70033

Xiangyi Kong, Wenyuan Lyu, Xiaojie Lin, Hao Feng, Lin Xu, Chengwei Li, Xinyi Sun, Chunlong Lin, Jianjun Li, Penghui Wei

{"title":"Transcranial direct current stimulation enhances the protective effect of isoflurane preconditioning on cerebral ischemia/reperfusion injury: A new mechanism associated with the nuclear protein Akirin2","authors":"Xiangyi Kong, Wenyuan Lyu, Xiaojie Lin, Hao Feng, Lin Xu, Chengwei Li, Xinyi Sun, Chunlong Lin, Jianjun Li, Penghui Wei","doi":"10.1111/cns.70033","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Aims</h3>\n \n <p>Ischemic stroke is a major cause of disability and mortality worldwide. Transcranial direct current stimulation (tDCS) and isoflurane (ISO) preconditioning exhibit neuroprotective properties. However, it remains unclear whether tDCS enhances the protective effect of ISO preconditioning on ischemic stroke, and the underlying mechanisms are yet to be clarified.</p>\n </section>\n \n <section>\n \n <h3> Method</h3>\n \n <p>A model of middle cerebral artery occlusion (MCAO), a rat ischemia–reperfusion (I/R) injury model, and an in vitro oxygen–glucose deprivation/re-oxygenation (O/R) model of ischemic injury were developed. ISO preconditioning and tDCS were administered daily for 7 days before MCAO modeling. Triphenyltetrazolium chloride staining, modified neurological severity score, and hanging-wire test were conducted to assess infarct volume and neurological outcomes. Untargeted metabolomic experiments, adeno-associated virus, lentiviral vectors, and small interfering RNA techniques were used to explore the underlying mechanisms.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>tDCS/DCS enhanced the protective effects of ISO pretreatment on I/R injury-induced brain damage. This was evidenced by reduced infarct volume and improved neurological outcomes in rats with MCAO, as well as decreased cortical neuronal death after O/R injury. Untargeted metabolomic experiments identified oxidative phosphorylation (OXPHOS) as a critical pathological process for ISO-mediated neuroprotection from I/R injury. The combination of tDCS/DCS with ISO preconditioning significantly inhibited I/R injury-induced OXPHOS. Mechanistically, Akirin2, a small nuclear protein that regulates cell proliferation and differentiation, was found to decrease in the cortex of rats with MCAO and in cortical primary neurons subjected to O/R injury. Akirin2 functions upstream of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). tDCS/DCS was able to further upregulate Akirin2 levels and activate the Akirin2/PTEN signaling pathway in vivo and in vitro, compared with ISO pretreatment alone, thereby contributing to the improvement of cerebral I/R injury.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>tDCS treatment enhances the neuroprotective effects of ISO preconditioning on ischemic stroke by inhibiting oxidative stress and activating Akirin2-PTEN signaling pathway, highlighting potential of combination therapy in ischemic stroke.</p>\n </section>\n </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 9","pages":""},"PeriodicalIF":4.8000,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70033","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"CNS Neuroscience & Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cns.70033","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

Aims

Ischemic stroke is a major cause of disability and mortality worldwide. Transcranial direct current stimulation (tDCS) and isoflurane (ISO) preconditioning exhibit neuroprotective properties. However, it remains unclear whether tDCS enhances the protective effect of ISO preconditioning on ischemic stroke, and the underlying mechanisms are yet to be clarified.

Method

A model of middle cerebral artery occlusion (MCAO), a rat ischemia–reperfusion (I/R) injury model, and an in vitro oxygen–glucose deprivation/re-oxygenation (O/R) model of ischemic injury were developed. ISO preconditioning and tDCS were administered daily for 7 days before MCAO modeling. Triphenyltetrazolium chloride staining, modified neurological severity score, and hanging-wire test were conducted to assess infarct volume and neurological outcomes. Untargeted metabolomic experiments, adeno-associated virus, lentiviral vectors, and small interfering RNA techniques were used to explore the underlying mechanisms.

Results

tDCS/DCS enhanced the protective effects of ISO pretreatment on I/R injury-induced brain damage. This was evidenced by reduced infarct volume and improved neurological outcomes in rats with MCAO, as well as decreased cortical neuronal death after O/R injury. Untargeted metabolomic experiments identified oxidative phosphorylation (OXPHOS) as a critical pathological process for ISO-mediated neuroprotection from I/R injury. The combination of tDCS/DCS with ISO preconditioning significantly inhibited I/R injury-induced OXPHOS. Mechanistically, Akirin2, a small nuclear protein that regulates cell proliferation and differentiation, was found to decrease in the cortex of rats with MCAO and in cortical primary neurons subjected to O/R injury. Akirin2 functions upstream of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). tDCS/DCS was able to further upregulate Akirin2 levels and activate the Akirin2/PTEN signaling pathway in vivo and in vitro, compared with ISO pretreatment alone, thereby contributing to the improvement of cerebral I/R injury.

Conclusion

tDCS treatment enhances the neuroprotective effects of ISO preconditioning on ischemic stroke by inhibiting oxidative stress and activating Akirin2-PTEN signaling pathway, highlighting potential of combination therapy in ischemic stroke.

Abstract Image

查看原文本刊更多论文

经颅直流电刺激可增强异氟醚预处理对脑缺血再灌注损伤的保护作用与核蛋白Akirin2有关的新机制

目的缺血性中风是全球致残和致死的主要原因。经颅直流电刺激（tDCS）和异氟烷（ISO）预处理具有神经保护特性。然而，经颅直流电刺激（tDCS）是否能增强异氟烷预处理对缺血性中风的保护作用仍不清楚，其潜在机制也有待明确。方法建立了大脑中动脉闭塞（MCAO）模型、大鼠缺血再灌注（I/R）损伤模型和体外氧-葡萄糖剥夺/再氧合（O/R）缺血性损伤模型。在MCAO模型建立前，每天进行ISO预处理和tDCS治疗7天。通过三苯基氯化四氮唑染色、改良神经系统严重程度评分和悬丝试验来评估梗死体积和神经系统预后。非靶向代谢组学实验、腺相关病毒、慢病毒载体和小干扰 RNA 技术被用来探索潜在的机制。结果 tDCS/DCS 增强了 ISO 预处理对 I/R 损伤诱导的脑损伤的保护作用。MCAO大鼠脑梗塞体积缩小、神经功能改善以及O/R损伤后皮质神经元死亡减少都证明了这一点。非靶向代谢组实验确定氧化磷酸化（OXPHOS）是 ISO 介导的 I/R 损伤神经保护的关键病理过程。将 tDCS/DCS 与 ISO 预处理相结合可显著抑制 I/R 损伤诱导的 OXPHOS。从机理上讲，研究发现Akirin2是一种调节细胞增殖和分化的小核蛋白，它在MCAO大鼠的大脑皮层和受到O/R损伤的大脑皮层初级神经元中减少。与单独使用 ISO 预处理相比，tDCS/DCS 能够进一步上调体内和体外 Akirin2 水平并激活 Akirin2/PTEN 信号通路，从而有助于改善脑 I/R 损伤。结论 tDCS治疗通过抑制氧化应激和激活Akirin2-PTEN信号通路，增强了ISO预处理对缺血性中风的神经保护作用，凸显了联合疗法在缺血性中风中的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.