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α7 nicotinic acetylcholine receptor agonist improved brain injury and impaired glucose metabolism in a rat model of ischemic stroke

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Abstract

Vagus nerve stimulation through the action of acetylcholine can modulate inflammatory responses and metabolism. α7 Nicotinic Acetylcholine Receptor (α7nAChR) is a key component in the biological functions of acetylcholine. To further explore the health benefits of vagus nerve stimulation, this study aimed to investigate whether α7nAChR agonists offer beneficial effects against poststroke inflammatory and metabolic changes and to identify the underlying mechanisms in a rat model of stroke established by permanent cerebral ischemia. We found evidence showing that pretreatment with α7nAChR agonist, GTS-21, improved poststroke brain infarction size, impaired motor coordination, brain apoptotic caspase 3 activation, dysregulated glucose metabolism, and glutathione reduction. In ischemic cortical tissues and gastrocnemius muscles with GTS-21 pretreatment, macrophages/microglia M1 polarization-associated Tumor Necrosis Factor-α (TNF-α) mRNA, Cluster of Differentiation 68 (CD68) protein, and Inducible Nitric Oxide Synthase (iNOS) protein expression were reduced, while expression of anti-inflammatory cytokine IL-4 mRNA, and levels of M2 polarization-associated CD163 mRNA and protein were increased. In the gastrocnemius muscles, stroke rats showed a reduction in both glutathione content and Akt Serine 473 phosphorylation, as well as an elevation in Insulin Receptor Substrate-1 Serine 307 phosphorylation and Dynamin-Related Protein 1 Serine 616 phosphorylation. GTS-21 reversed poststroke changes in the gastrocnemius muscles. Overall, our findings, provide further evidence supporting the neuroprotective benefits of α7nAChR agonists, and indicate that they may potentially exert anti-inflammatory and metabolic effects peripherally in the skeletal muscle in an acute ischemic stroke animal model.

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Funding

This study was supported by grants from Taichung Veterans General Hospital (TCVGH-1115701D, 1118201 C), Hung Kuang University (TCVGH-HK1098001, 1088002), the Ministry of Science and Technology (MOST 110-2314-B-075 A-003-MY3), and Feng Yuan Hospital (Hospital and Social Welfare Organizations Administration Commission)/Ministry of Health and Welfare, Taiwan.

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Authors and Affiliations

  1. Department of Family Medicine, Taichung Veterans General Hospital, 407, Taichung City, Taiwan

    Ya-Yu Wang

  2. Center for Geriatrics and Gerontology, Taichung Veterans General Hospital, 407, Taichung City, Taiwan

    Shih-Yi Lin

  3. Institute of Clinical Medicine, National Yang Ming Chiao Tung University, 112, Taipei City, Taiwan

    Shih-Yi Lin

  4. Department of Surgery, Feng Yuan Hospital, 420, Taichung City, Taiwan

    Cheng-Yi Chang

  5. Department of Veterinary Medicine, National Chung Hsing University, 402, Taichung City, Taiwan

    Cheng-Yi Chang, Wen-Ying Chen & Wei-Chi Huang

  6. Department of Anesthesiology, Taichung Veterans General Hospital, 407, Taichung City, Taiwan

    Chih-Cheng Wu

  7. Department of Medical Research, Taichung Veterans General Hospital, No. 1650, Sec. 4, Taiwan Boulevard, 407, Taichung City, Taiwan

    Su-Lan Liao & Chun-Jung Chen

  8. Department of Nursing, Hung Kuang University, 433, Taichung City, Taiwan

    Wen-Yi Wang

  9. Department of Medical Laboratory Science and Biotechnology, China Medical University, 404, Taichung City, Taiwan

    Chun-Jung Chen

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Contributions

YYW and CJC designed the study, YYW, SYL, CYC, CCW, WYC, WCH, SLL, and WYW conducted the experiments, YYW drafted the original manuscript, CJC revised the manuscript, and CJC supervised the study. All authors read and approved the final manuscript and agreed to the submission.

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Correspondence to Chun-Jung Chen.

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The authors have no relevant financial or non-financial interests to disclose.

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The protocols for the animal study were reviewed and approved by The Animal Experimental Committee of Taichung Veterans General Hospital (IACUC approval code: La-1091967; IACUC approval date: Feb. 17, 2020).

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Wang, YY., Lin, SY., Chang, CY. et al. α7 nicotinic acetylcholine receptor agonist improved brain injury and impaired glucose metabolism in a rat model of ischemic stroke. Metab Brain Dis 38, 1249–1259 (2023). https://doi.org/10.1007/s11011-023-01167-w

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