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The role of isoleucine in cerebral ischemia\u2013reperfusion injury remains unclear. Here, we show that the concentration of isoleucine is decreased in cerebrospinal fluid in a rat model of cerebral ischemia\u2013reperfusion injury, the rat middle cerebral artery occlusion (MCAO). To our surprise, the level of intraneuronal isoleucine is increased in an in vitro model of cerebral ischemia injury, the oxygen\u2013glucose deprivation (OGD). We found that the increased activity of LAT1, an L\u2010type amino acid transporter 1, leads to the elevation of intraneuronal isoleucine after OGD insult. Reducing the level of intraneuronal isoleucine promotes cell survival after cerebral ischemia\u2013reperfusion injury, but supplementing isoleucine aggravates the neuronal damage. To understand how isoleucine promotes ischemia\u2010induced neuronal death, we reveal that isoleucine acts upstream to reduce the expression of CBFB (core binding factor \u03b2, a transcript factor involved in cell development and growth) and that the phosphatase PTEN acts downstream of CBFB to mediate isoleucine\u2010induced neuronal damage after OGD insult. Interestingly, we demonstrate that direct\u2010current stimulation reduces the level of intraneuronal isoleucine in cortical cultures subjected to OGD and that transcranial direct\u2010current stimulation (tDCS) decreases the cerebral infarct volume of MCAO rat through reducing LAT1\u2010depencent increase of intraneuronal isoleucine. Together, these results lead us to conclude that LAT1 over activation\u2010dependent isoleucine\u2010CBFB\u2010PTEN signal transduction pathway may mediate ischemic neuronal injury and that tDCS exerts its neuroprotective effect by suppressing LAT1 over activation\u2010dependent signalling after cerebral ischemia\u2013reperfusion injury.<\/jats:p>","DOI":"10.1111\/ejn.16091","type":"journal-article","created":{"date-parts":[[2023,7,15]],"date-time":"2023-07-15T04:34:32Z","timestamp":1689395672000},"page":"3330-3346","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Transcranial direct\u2010current stimulation confers neuroprotection by regulating isoleucine\u2010dependent signalling after rat cerebral ischemia\u2013reperfusion injury"],"prefix":"10.1111","volume":"58","author":[{"given":"Xujin","family":"Yao","sequence":"first","affiliation":[{"name":"Institute of Neuroregeneration and Neurorehabilitation, Department of Pathophysiology Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyi","family":"Kong","sequence":"additional","affiliation":[{"name":"Institute of Neuroregeneration and Neurorehabilitation, Department of Pathophysiology Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyang","family":"Ren","sequence":"additional","affiliation":[{"name":"Institute of Neuroregeneration and Neurorehabilitation, Department of Pathophysiology Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Cui","sequence":"additional","affiliation":[{"name":"Institute of Neuroregeneration and Neurorehabilitation, Department of Pathophysiology Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songfeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingchen","family":"Gao","sequence":"additional","affiliation":[{"name":"Institute of Neuroregeneration and Neurorehabilitation, Department of Pathophysiology Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangdong","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Neuroregeneration and Neurorehabilitation, Department of Pathophysiology Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Affiliated Hospital of Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Hu","sequence":"additional","affiliation":[{"name":"Institute of Neuroregeneration and Neurorehabilitation, Department of Pathophysiology Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanting","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Neuroregeneration and Neurorehabilitation, Department of Pathophysiology Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengyuan","family":"Che","sequence":"additional","affiliation":[{"name":"Central Laboratory, Department of Neurology, Linyi People's Hospital Qingdao University  Linyi Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1327-9851","authenticated-orcid":false,"given":"Qi","family":"Wan","sequence":"additional","affiliation":[{"name":"Institute of Neuroregeneration and Neurorehabilitation, Department of Pathophysiology Qingdao University  Qingdao China"},{"name":"Qingdao Gui\u2010Hong Intelligent Medical Technology Co. 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