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Delayed Chronic Acidic Postconditioning Improves Poststroke Motor Functional Recovery and Brain Tissue Repair by Activating Proton-Sensing TDAG8

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Abstract

Acidic postconditioning by transient CO2 inhalation applied within minutes after reperfusion has neuroprotective effects in the acute phase of stroke. However, the effects of delayed chronic acidic postconditioning (DCAPC) initiated during the subacute phase of stroke or other acute brain injuries are unknown. Mice received daily DCAPC by inhaling 5%/10%/20% CO2 for various durations (three cycles of 10- or 20-min CO2 inhalation/10-min break) at days 3–7, 7–21, or 3–21 after photothrombotic stroke. Grid-walk, cylinder, and gait tests were used to assess motor function. DCAPC with all CO2 concentrations significantly promoted motor functional recovery, even when DCAPC was delayed for 3–7 days. DCAPC enhanced the puncta density of GAP-43 (a marker of axon growth and regeneration) and synaptophysin (a marker of synaptogenesis) and reduced the amoeboid microglia number, glial scar thickness and mRNA expression of CD16 and CD32 (markers of proinflammatory M1 microglia) compared with those of the stroke group. Cerebral blood flow (CBF) increased in response to DCAPC. Furthermore, the mRNA expression of TDAG8 (a proton-activated G-protein-coupled receptor) was increased during the subacute phase of stroke, while DCAPC effects were blocked by systemic knockout of TDAG8, except for those on CBF. DCAPC reproduced the benefits by re-expressing TDAG8 in the peri-infarct cortex of TDAG8-/- mice infected with HBAAV2/9-CMV-TDAG8-3flag-ZsGreen. Taken together, we first showed that DCAPC promoted functional recovery and brain tissue repair after stroke with a wide therapeutic time window of at least 7 days after stroke. Brain-derived TDAG8 is a direct target of DCAPC that induces neuroreparative effects.

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Funding

This work was sponsored by the National Natural Science Foundation of China (81872854, 81202520), the Open Fund from the Key Laboratory of Cellular Physiology (Shanxi Medical University, KLCP2019), and the Fund for Shanxi “1331 Project” Key Subjects Construction.

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  1. Yan-Ying Fan, Yu Li, Xiao-Ying Tian, and Ying-Jing Wang contributed equally to this work.

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  1. Department of Pharmacology, Basic Medical Sciences Center, Shanxi Medical University, Taiyuan, 030001, China

    Yan-Ying Fan, Yu Li, Xiao-Ying Tian, Ying-Jing Wang, Jing Huo, Bao-Lu Guo, Ru Chen, Cai-Hong Yang, Yan Li, Hui-Feng Zhang, Bao-Long Niu & Ming-Sheng Zhang

  2. Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, China

    Yan-Ying Fan

  3. College of Materials Science and Engineering, Taiyuan University of Technology, Taiyuan, 030024, China

    Bao-Long Niu

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Conceptualization: Yan-Ying Fan, Ming-Sheng Zhang; methodology: Yu Li, Xiao-Ying Tian, Ying-Jing Wang, Bao-Lu Guo, Jing Huo, Ru Chen, Hui-Feng Zhang; data curation: Yan-Ying Fan, Yan Li, Cai-Hong Yang; formal analysis and investigation: Yan-Ying Fan, Yan Li, Cai-Hong Yang; writing—original draft preparation: Yan-Ying Fan; writing—review and editing: Bao-Long Niu and Ming-Sheng Zhang; funding acquisition: Yan-Ying Fan.

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Correspondence to Yan-Ying Fan, Bao-Long Niu or Ming-Sheng Zhang.

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Fan, YY., Li, Y., Tian, XY. et al. Delayed Chronic Acidic Postconditioning Improves Poststroke Motor Functional Recovery and Brain Tissue Repair by Activating Proton-Sensing TDAG8. Transl. Stroke Res. (2023). https://doi.org/10.1007/s12975-023-01143-7

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