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Sappanone A Protects Against Inflammation, Oxidative Stress and Apoptosis in Cerebral Ischemia-Reperfusion Injury by Alleviating Endoplasmic Reticulum Stress

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Abstract

Endoplasmic reticulum stress is an important contributor to the cerebral ischemic injury. Sappanone A (SA), a kind of natural homoisoflavanone extracted from Caesalpinia sappan L, has been evidenced to exhibit anti-inflammatory and antioxidative properties. The present study aimed to investigate the potential neuroprotective effects of SA in cerebral ischemia-reperfusion injury. The potential neuroprotective effect of SA was tested in a rat model of middle cerebral artery occlusion (MCAO) allowing reperfusion and PC12 cell model of oxygen-glucose deprivation and reperfusion (OGD/R). Post-ischemic neuronal injury was evaluated by 2, 3, 5-triphenyltetrazolium chloride (TTC) and hematoxylin-eosin (H&E) staining. The levels of inflammatory factors and oxidative stress-related markers were detected using corresponding kits. Cell apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) or flow cytometry, and the expression of apoptosis-associated proteins was determined using western blot analysis. Subsequently, endoplasmic reticulum stress-related proteins were detected through western blot analysis, and CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) was overexpressed to confirm the contribution of endoplasmic reticulum stress inhibition by SA to the neuroprotective effects post OGD/R. Results revealed that SA was effective in ameliorating cerebral infarction and pathological injuries post-reperfusion following MCAO, which is associated with reduced inflammation, oxidative stress, and cell apoptosis by SA in the brain. Consistently, these neuroprotective effects of SA post ischemia-reperfusion were also observed in a PC12 cell model of OGD/R. Importantly, endoplasmic reticulum stressors, including the CHOP, the 78 kDa glucose-regulated protein 78 (GRP78), and phosphorylated eukaryotic initiation factors 2α (EIF-2α), were significantly downregulated by SA, while CHOP overexpression attenuated the beneficial effects of SA on inflammation, oxidative stress, and apoptosis in OGD/R-induced PC12 cells. These results demonstrated that SA alleviates endoplasmic reticulum stress, ameliorating inflammation, oxidative stress, and apoptosis, and thereby serves as therapeutic potential for protection against cerebral ischemia-reperfusion injury in ischemic stroke.

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All data present in the paper is available for reasonable request to the corresponding author.

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Authors and Affiliations

  1. Department of Neurosurgery & Neurocritical Care, Huashan Hospital Affiliated to Fudan University, Shanghai, 200040, China

    Meihua Wang & Lei Yang

  2. Department of Neurology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China

    Meihua Wang

  3. Department of Neurology, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200081, China

    Zhilin Chen

  4. Preventive Medicine Department, Qingdao Hospital of Traditional Chinese Medicine (Qingdao Hiser Hospital), Room 401, 73 Lijin Road, Shibei District, Qingdao, 266000, Shandong, China

    Lei Ding

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  1. Meihua Wang
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Contributions

Meihua Wang and Zhilin Chen designed this study, performed experiments, and interpreted the data. Lei Yang collected the data, searched the literature, and wrote the manuscript. Lei Ding revised the manuscript. All authors read and approval the final manuscript.

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Correspondence to Lei Ding.

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All animal studies were approved by the Animal Care and Use Committee of Huashan Hospital Affiliated to Fudan University.

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Wang, M., Chen, Z., Yang, L. et al. Sappanone A Protects Against Inflammation, Oxidative Stress and Apoptosis in Cerebral Ischemia-Reperfusion Injury by Alleviating Endoplasmic Reticulum Stress. Inflammation 44, 934–945 (2021). https://doi.org/10.1007/s10753-020-01388-6

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