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tDCS Regulates ASBT-3-OxoLCA-PLOD2-PTEN Signaling Pathway to Confer Neuroprotection Following Rat Cerebral Ischemia-Reperfusion Injury

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Abstract

Humans exhibit a rich intestinal microbiome that contain high levels of bacteria capable of producing 3-oxo-lithocholic acid (3-oxoLCA) and other secondary bile acids (BAs). The molecular mechanism mediating the role of 3-oxoLCA in cerebral ischemia-reperfusion (I/R) injury remains unclear. We investigated the role of 3-oxoLCA in a rat cerebral I/R injury model. We found that the concentrations of 3-oxoLCA within the cerebrospinal fluid were increased following I/R. In the in vitro oxygen-glucose deprivation (OGD) model, the levels of intraneuronal 3-oxoLCA was elevated following OGD insult. We showed that the increase of membrane ASBT (apical sodium-dependent bile acid transporter) contributed to OGD-induced elevation of intraneuronal 3-oxoLCA. Increasing intraneuronal 3-oxoLCA promoted ischemia-induced neuronal death, whereas reducing 3-oxoLCA levels were neuroprotective. Our results revealed that PLOD2 (procollagen-lysine, 2-oxoglutarate 5-dioxygenases 2) functioned upstream of PTEN (the phosphatase and tensin homolog deleted on chromosome 10) and downstream of 3-oxoLCA to promote OGD-induced neuronal injury. We further demonstrated that direct-current stimulation (DCS) decreased the levels of intraneuronal 3-oxoLCA and membrane ASBT in OGD-insulted neurons, while bilateral transcranial DCS (tDCS) reduced brain infarct volume following I/R by inhibiting ASBT. Together, these data suggest that increased expression of ASBT promotes neuronal death via 3-oxoLCA-PLOD2-PTEN signaling pathway. Importantly, bilateral tDCS suppresses ischemia-induced increase of ASBT, thereby conferring neuroprotection after cerebral I/R injury.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. Some data may not be made available because of privacy or ethical restrictions.

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Funding

This work was supported by the National Key R&D Program of China (2019YFC0120000; 2018YFC1312300), the National Natural Science Foundation of China (NSFC: 82071385), the Key Research and Development Project of Shandong (2019JZZY021010), and the TaiShan Industrial Experts Programme (No. tscy20200412) to Q.W.

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Authors and Affiliations

  1. Institute of Neuroregeneration & Neurorehabilitation, Department of Neurosurgery, Qingdao University, 308 Ningxia Street, Qingdao, 266071, China

    Xiangyi Kong, Xujin Yao, Jinyang Ren, Jingchen Gao, Yu Cui, Jiangdong Sun, Xiangyu Xu, Wenjie Hu, Hui Wang, Huanting Li & Qi Wan

  2. Department of Old Age Psychiatry, The Institute of Psychiatry, Psychology & Neuroscience, King’s College London, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK

    Oleg O. Glebov

  3. Central Laboratory, Department of Neurology, Linyi People’s Hospital, Qingdao University, 27 East Jiefang Road, Linyi, Shandong, China

    Fengyuan Che

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Contributions

XK and XY performed the experiment, analyzed data, and wrote the manuscript. JR, JG, YC, JS, and XX performed the in vivo experiments and analyzed the data. WH, HW, and OG performed the in vitro experiments and analyzed the data. FC and QW conceived the project and wrote the manuscript.

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Correspondence to Fengyuan Che or Qi Wan.

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Kong, X., Yao, X., Ren, J. et al. tDCS Regulates ASBT-3-OxoLCA-PLOD2-PTEN Signaling Pathway to Confer Neuroprotection Following Rat Cerebral Ischemia-Reperfusion Injury. Mol Neurobiol 60, 6715–6730 (2023). https://doi.org/10.1007/s12035-023-03504-7

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