Dexmedetomidine Protects the Brain: Exploring the α2AR/FAK Pathway in Post-Stroke Intestinal Barrier Repair
Introduction: Globally, ischemic stroke is a major cause of mortality and disability, posing a significant challenge in clinical practice and public health. Recent studies have reported that stroke leads to the impairment of the intestinal barrier and the migration of intestinal b...
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IMR Press
2025-02-01
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| Series: | Frontiers in Bioscience-Landmark |
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| Online Access: | https://www.imrpress.com/journal/FBL/30/2/10.31083/FBL27159 |
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| author | Xinting Zhou Yan Yang Zixuan Su Zhonghui Luo |
| author_facet | Xinting Zhou Yan Yang Zixuan Su Zhonghui Luo |
| author_sort | Xinting Zhou |
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| description | Introduction: Globally, ischemic stroke is a major cause of mortality and disability, posing a significant challenge in clinical practice and public health. Recent studies have reported that stroke leads to the impairment of the intestinal barrier and the migration of intestinal bacteria to multiple organs. This process exacerbates neurological damage by further impairing intestinal barrier function and leading to bacterial translocation. Dexmedetomidine (Dex), an α2-adrenoceptor (α2AR) agonist, has proven anti-cerebral ischemic effects, yet its effects in post-stroke intestinal dysfunction remain unclear. This study aimed to determine whether Dex mitigates intestinal dysfunction and brain injury following cerebral ischemia-reperfusion. Methods: A C57BL/6J mouse model of middle cerebral artery occlusion (MCAO) was used for in vivo experiments, while lipopolysaccharide (LPS)-induced Caco-2 monolayers served as an in vitro model of intestinal barrier dysfunction. Neuronal apoptosis was evaluated using neuronal nuclei (NeuN) and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) double labeling. Reverse transcription-quantitative PCR (RT-qPCR) was performed to measure pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. Intestinal permeability was assessed using histological score, serum fluorescein isothiocyanate (FITC)-dextran fluorescence, and endotoxin levels. The expression levels of epithelial cadherin (E-cadherin), zonula occludens-1 (ZO-1), and occludin were analyzed by western blot and immunofluorescence. Statistical analyses included analysis of variance with Tukey’s post-hoc test. Results: Dex treatment significantly reduced cerebral infarct volume (p < 0.001) and improved neurological scores compared to MCAO controls. Neuronal apoptosis was significantly inhibited (p < 0.01), as evidenced by reduced TUNEL-positive cells in Dex-treatment MCAO mice. TNF-α, IL-1β and IL-6 were markedly downregulated (p < 0.05). While MCAO increased intestinal permeability (elevated serum FITC-dextran and endotoxin levels, p < 0.01), Dex treatment restored barrier integrity. Dex upregulated E-cadherin expression significantly (p < 0.05) but did not restore the decreased levels of ZO-1 and occludin following MCAO. Dex promoted intestinal permeability repair and alleviated brain injury via the α2AR/focal adhesion kinase (FAK) pathway in MCAO mice. Similarly, Dex mitigated LPS-induced barrier dysfunction in Caco-2 monolayers by restoring FAK expression and improving intestinal barrier integrity. Conclusions: Dex alleviates post-stroke intestinal barrier dysfunction and mitigates brain injury, possibly through activating the α2AR/FAK pathway. These findings underscore a potential therapeutic strategy for addressing secondary complications of ischemic stroke and improving patient outcomes. |
| format | Article |
| id | doaj-art-c2d810cb3aca44638379b5017875a7c7 |
| institution | OA Journals |
| issn | 2768-6701 |
| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-c2d810cb3aca44638379b5017875a7c72025-08-20T02:00:29ZengIMR PressFrontiers in Bioscience-Landmark2768-67012025-02-013022715910.31083/FBL27159S2768-6701(25)01637-5Dexmedetomidine Protects the Brain: Exploring the α2AR/FAK Pathway in Post-Stroke Intestinal Barrier RepairXinting Zhou0Yan Yang1Zixuan Su2Zhonghui Luo3Department of Anaesthesiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, ChinaDepartment of Anaesthesiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, ChinaDepartment of Anaesthesiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, ChinaDepartment of Anaesthesiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, ChinaIntroduction: Globally, ischemic stroke is a major cause of mortality and disability, posing a significant challenge in clinical practice and public health. Recent studies have reported that stroke leads to the impairment of the intestinal barrier and the migration of intestinal bacteria to multiple organs. This process exacerbates neurological damage by further impairing intestinal barrier function and leading to bacterial translocation. Dexmedetomidine (Dex), an α2-adrenoceptor (α2AR) agonist, has proven anti-cerebral ischemic effects, yet its effects in post-stroke intestinal dysfunction remain unclear. This study aimed to determine whether Dex mitigates intestinal dysfunction and brain injury following cerebral ischemia-reperfusion. Methods: A C57BL/6J mouse model of middle cerebral artery occlusion (MCAO) was used for in vivo experiments, while lipopolysaccharide (LPS)-induced Caco-2 monolayers served as an in vitro model of intestinal barrier dysfunction. Neuronal apoptosis was evaluated using neuronal nuclei (NeuN) and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) double labeling. Reverse transcription-quantitative PCR (RT-qPCR) was performed to measure pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. Intestinal permeability was assessed using histological score, serum fluorescein isothiocyanate (FITC)-dextran fluorescence, and endotoxin levels. The expression levels of epithelial cadherin (E-cadherin), zonula occludens-1 (ZO-1), and occludin were analyzed by western blot and immunofluorescence. Statistical analyses included analysis of variance with Tukey’s post-hoc test. Results: Dex treatment significantly reduced cerebral infarct volume (p < 0.001) and improved neurological scores compared to MCAO controls. Neuronal apoptosis was significantly inhibited (p < 0.01), as evidenced by reduced TUNEL-positive cells in Dex-treatment MCAO mice. TNF-α, IL-1β and IL-6 were markedly downregulated (p < 0.05). While MCAO increased intestinal permeability (elevated serum FITC-dextran and endotoxin levels, p < 0.01), Dex treatment restored barrier integrity. Dex upregulated E-cadherin expression significantly (p < 0.05) but did not restore the decreased levels of ZO-1 and occludin following MCAO. Dex promoted intestinal permeability repair and alleviated brain injury via the α2AR/focal adhesion kinase (FAK) pathway in MCAO mice. Similarly, Dex mitigated LPS-induced barrier dysfunction in Caco-2 monolayers by restoring FAK expression and improving intestinal barrier integrity. Conclusions: Dex alleviates post-stroke intestinal barrier dysfunction and mitigates brain injury, possibly through activating the α2AR/FAK pathway. These findings underscore a potential therapeutic strategy for addressing secondary complications of ischemic stroke and improving patient outcomes.https://www.imrpress.com/journal/FBL/30/2/10.31083/FBL27159strokebrainintestinal barrieralpha2-adrenoceptorfocal adhesion kinase |
| spellingShingle | Xinting Zhou Yan Yang Zixuan Su Zhonghui Luo Dexmedetomidine Protects the Brain: Exploring the α2AR/FAK Pathway in Post-Stroke Intestinal Barrier Repair Frontiers in Bioscience-Landmark stroke brain intestinal barrier alpha2-adrenoceptor focal adhesion kinase |
| title | Dexmedetomidine Protects the Brain: Exploring the α2AR/FAK Pathway in Post-Stroke Intestinal Barrier Repair |
| title_full | Dexmedetomidine Protects the Brain: Exploring the α2AR/FAK Pathway in Post-Stroke Intestinal Barrier Repair |
| title_fullStr | Dexmedetomidine Protects the Brain: Exploring the α2AR/FAK Pathway in Post-Stroke Intestinal Barrier Repair |
| title_full_unstemmed | Dexmedetomidine Protects the Brain: Exploring the α2AR/FAK Pathway in Post-Stroke Intestinal Barrier Repair |
| title_short | Dexmedetomidine Protects the Brain: Exploring the α2AR/FAK Pathway in Post-Stroke Intestinal Barrier Repair |
| title_sort | dexmedetomidine protects the brain exploring the α2ar fak pathway in post stroke intestinal barrier repair |
| topic | stroke brain intestinal barrier alpha2-adrenoceptor focal adhesion kinase |
| url | https://www.imrpress.com/journal/FBL/30/2/10.31083/FBL27159 |
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