2. Academic Validation
  3. Targeting astrocytic TDAG8 with delayed CO2 postconditioning improves functional outcomes after controlled cortical impact injury in mice

Targeting astrocytic TDAG8 with delayed CO2 postconditioning improves functional outcomes after controlled cortical impact injury in mice

  • Exp Neurol. 2024 Oct:380:114892. doi: 10.1016/j.expneurol.2024.114892.
Shu-Han Zhang 1,  Jing Yin 1,  Lian-Ju Jing 1,  Yao Cheng 1,  Yu-Lu Miao 2,  Bo Fan 3,  Hui-Feng Zhang 1,  Cai-Hong Yang 1,  Shao-Shuai Wang 4,  Yan Li 5,  Xiang-Ying Jiao 6,  Yan-Ying Fan 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medical Science, Shanxi Medical University, Taiyuan 030001, Shanxi, China.
  • 2 Department of Pharmacology, School of Basic Medical Science, Shanxi Medical University, Taiyuan 030001, Shanxi, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi, China.
  • 3 Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China.
  • 4 Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan 030001, China.
  • 5 Department of Pharmacology, School of Basic Medical Science, Shanxi Medical University, Taiyuan 030001, Shanxi, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi, China. Electronic address: sxliyan@sxmu.edu.
  • 6 Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi, China. Electronic address: jiaoxy@sxmu.edu.cn.
  • 7 Department of Pharmacology, School of Basic Medical Science, Shanxi Medical University, Taiyuan 030001, Shanxi, China; Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China. Electronic address: fanyanying@sxmu.edu.cn.
PMID: 39047809 DOI: 10.1016/j.expneurol.2024.114892
Abstract

T-cell death-associated gene 8 (TDAG8), a G-protein-coupled receptor sensing physiological or weak acids, regulates inflammatory responses. However, its role in traumatic brain injury (TBI) remains unknown. Our recent study showed that delayed CO2 postconditioning (DCPC) has neuroreparative effects after TBI. We hypothesized that activating astrocytic TDAG8 is a key mechanism for DCPC. WT and TDAG8-/- mice received DCPC daily by transiently inhaling 10% CO2 after controlled cortical impact (CCI). HBAAV2/9-GFAP-m-TDAG8-3xflag-EGFP was used to overexpress TDAG8 in astrocytes. The beam walking test, mNSS, immunofluorescence and Golgi-Cox staining were used to evaluate motor function, glial activation and dendritic plasticity. DCPC significantly improved motor function; increased total dendritic length, neuronal complexity and spine density; inhibited overactivation of astrocytes and microglia; and promoted the expression of astrocytic brain-derived neurotrophic factor in WT but not TDAG8-/- mice. Overexpressing TDAG8 in astrocytes surrounding the lesion in TDAG8-/- mice restored the beneficial effects of DCPC. Although the effects of DCPC on Days 14-28 were much weaker than those of DCPC on Days 3-28 in WT mice, these effects were further enhanced by overexpressing astrocytic TDAG8. Astrocytic TDAG8 is a key target of DCPC for TBI rehabilitation. Its overexpression is a strategy that broadens the therapeutic window and enhances the effects of DCPC.

Keywords

Astrocytic TDAG8; CO(2) inhalation; Dendritic plasticity; Motor functional recovery; Neuroreparative strategy; Therapeutic window; Traumatic brain injury.

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