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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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>A model of middle cerebral artery occlusion (MCAO), a rat ischemia\u2013reperfusion (I\/R) injury model, and an in\u00a0vitro oxygen\u2013glucose deprivation\/re\u2010oxygenation (O\/R) model of ischemic injury were developed. ISO preconditioning and tDCS were administered daily for 7\u2009days before MCAO modeling. Triphenyltetrazolium chloride staining, modified neurological severity score, and hanging\u2010wire test were conducted to assess infarct volume and neurological outcomes. Untargeted metabolomic experiments, adeno\u2010associated virus, lentiviral vectors, and small interfering RNA techniques were used to explore the underlying mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>tDCS\/DCS enhanced the protective effects of ISO pretreatment on I\/R injury\u2010induced 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\u2010mediated neuroprotection from I\/R injury. The combination of tDCS\/DCS with ISO preconditioning significantly inhibited I\/R injury\u2010induced 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\u00a0vivo and in\u00a0vitro, compared with ISO pretreatment alone, thereby contributing to the improvement of cerebral I\/R injury.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>tDCS treatment enhances the neuroprotective effects of ISO preconditioning on ischemic stroke by inhibiting oxidative stress and activating Akirin2\u2010PTEN signaling pathway, highlighting potential of combination therapy in ischemic stroke.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70033","type":"journal-article","created":{"date-parts":[[2024,9,13]],"date-time":"2024-09-13T04:54:09Z","timestamp":1726203249000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"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"],"prefix":"10.1111","volume":"30","author":[{"given":"Xiangyi","family":"Kong","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine Shandong University  Qingdao China"},{"name":"Laboratory of Anesthesia and Brain Function, Qilu Hospital (Qingdao), Cheeloo College of Medicine Shandong University  Qingdao China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenyuan","family":"Lyu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine Shandong University  Qingdao China"},{"name":"Laboratory of Anesthesia and Brain Function, Qilu Hospital (Qingdao), Cheeloo College of Medicine Shandong University  Qingdao 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