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经颅直流电刺激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 相关的新机制。

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.

机构信息

Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China.

Laboratory of Anesthesia and Brain Function, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China.

出版信息

CNS Neurosci Ther. 2024 Sep;30(9):e70033. doi: 10.1111/cns.70033.

DOI:10.1111/cns.70033
PMID:39267282
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11393012/
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.

摘要

目的

缺血性脑卒中是全球范围内导致残疾和死亡的主要原因。经颅直流电刺激（tDCS）和异氟烷（ISO）预处理均表现出神经保护作用。然而，tDCS 是否增强 ISO 预处理对缺血性脑卒中的保护作用尚不清楚，其潜在机制仍有待阐明。

方法

建立大脑中动脉闭塞（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/再复氧（O/R）缺血损伤模型。在 MCAO 模型建立前，每天给予 ISO 预处理和 tDCS 治疗，共 7 天。采用氯化三苯基四氮唑染色、改良神经功能缺损评分和悬线试验评估梗死体积和神经功能结局。非靶向代谢组学实验、腺相关病毒、慢病毒载体和小干扰 RNA 技术用于探索潜在机制。

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。这表现在 MCAO 大鼠的梗死体积减小，神经功能结局改善，以及 O/R 损伤后皮质神经元死亡减少。非靶向代谢组学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。tDCS/DCS 与 ISO 预处理联合显著抑制 I/R 损伤诱导的 OXPHOS。机制上，Akirin2，一种调节细胞增殖和分化的小核蛋白，在 MCAO 大鼠皮质和 O/R 损伤的皮质原代神经元中减少。Akirin2 位于磷酸酶和张力蛋白同源物缺失于染色体 10（PTEN）上游。与 ISO 预处理相比，tDCS/DCS 能够进一步上调 Akirin2 水平并激活体内和体外的 Akirin2/PTEN 信号通路，从而改善脑 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 ISO 预处理对缺血性脑卒中的神经保护作用，提示联合治疗在缺血性脑卒中中有潜在应用价值。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a10/11393012/9f610f416b47/CNS-30-e70033-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a10/11393012/81e0d8032f73/CNS-30-e70033-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a10/11393012/728ba7d9e707/CNS-30-e70033-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a10/11393012/9f610f416b47/CNS-30-e70033-g005.jpg

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