• Shock · Dec 2024

    Gastrodin protects against sepsis-associated encephalopathy by suppressing ferroptosis.

    • Yunfei Xu, Jing Chen, Lin Zhou, Yao Zhao, Nina He, Qing Xu, Jie Zhao, and Ying Liu.
    • Department of Pathology and Pathophysiology, Faculty of Basic Medical Science, Kunming Medical University, Kunming 650500, Yunnan, China.
    • Shock. 2024 Dec 17.

    BackgroundSepsis-associated encephalopathy (SAE) represents a severe complication of sepsis, substantially elevating both mortality and healthcare costs for patients. Gastrodin (GAS), a principal bioactive constituent of Gastrodia elata Blume, is neuroprotective in various neurological disorders, including ischemic stroke, epilepsy, Alzheimer's disease, and neuropathic pain. In this study, we sought to investigate whether GAS could serve as a protective agent against SAE.MethodsMice were subjected to cecal ligation and puncture (CLP) or the murine brain microvascular endothelial cell bEnd.3 was exposed to lipopolysaccharide (LPS) and subsequently treated with GAS. We assessed neurological deficits, blood-brain barrier (BBB) integrity, neuroinflammation, and the state of ferroptosis to evaluate the regulation of GAS on SAE. Mechanistically, we utilized glutathione peroxidase 4 (GPX4) knockout mice to delineate the crucial role of GPX4 and examined the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway to uncover the upstream signaling of GPX4.ResultsGAS mitigated neurological deficits in SAE mice and reduced BBB disruption and neuroinflammation both in vivo and in vitro. Functionally, the neuroprotective effects of GAS were realized through the inhibition of ferroptosis. Furthermore, we demonstrated that GPX4 played a pivotal role in this process. Lastly, we found that the COX-2/PGE2 pathway was activated following GAS treatment in SAE mice, thereby increasing the expression level of GPX4.ConclusionsOur study elucidated that GAS offers protection against SAE by suppressing ferroptosis through the activation of the COX-2/PGE2/GPX4 axis. This research validates the therapeutic potential of GAS and provides novel insights into potential therapeutic strategies for the management of SAE.Copyright © 2024 by the Shock Society.

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