• Ziwen Chen, Fuwei Wang, Zihao Chen, Nan Zheng, Qiu Zhou, Lihua Xie, Qiang Sun, Li Li, and Baohong Li.
• Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, The Affiliated Dongguan Songshan Lake Central Hospital, School of Pharmacy, Guangdong Medical University, Dongguan, China.
• Neuroscience. 2024 Nov 1; 559: 139149139-149.

AbstractAlzheimer's disease (AD) is the most common form of neurodegeneration which currently has no effective treatment. Ferroptosis is a new style of programmed cell death and is widely implicated in the pathogenesis and progression of AD. Decursin has been shown widely neuroprotective effects but poorly understood about the underlying mechanisms between decursin and ferroptosis in AD. Here, the protective effect of decursin and the underlying mechanism under glutamate treatment in SH-SY5Y cells was investigated. SH-SY5Y cells were cultured with glutamate in the presence or absence of decursin. The safe concentrations of decursin on SH-SY5Y cells were measured via CCK-8. Furthermore, LDH content, antioxidant enzyme activities including GPx, CAT and SOD, MDA contents, GSH levels, ROS formation, MMP, mitochondria ultrastructure morphology change, and intracellular Fe2+ levels were measured to investigate the influence of decursin and Fer-1 on ferroptosis in glutamate-treated SH-SY5Y cells. Moreover, the expressions of ferroptosis-related proteins were determined by Western blot. As a result, glutamate-induced cell survival was markedly elevated and morphological change was improved by decursin administrated in SH-SY5Y cells. Furthermore, decursin could reversed the decreased antioxidant enzyme activities, GSH levels, GPX4n and FTH1 expression, as well as the increased iron levels, LDH, MDA, ROS formation, and MMP, which showed similar effects to Fer-1, the specific ferroptosis inhibitor. Therefore, the inhibitory effect of decursin on ferroptosis probably was partially governed by FTH1 expression to regulate the cellular iron homeostasis. Additionally, decursin facilitated the translocation of Nrf2 from the cytoplasm to the nucleus. Taken together, our data for the first time suggest that decursin could ameliorate neurotoxicity induced by glutamate by attenuating ferroptosis via alleviating cellular iron levels by up-regulating FTH1 expression which is attributing to its promotion of Nrf2 translocation into the nucleus in SH-SY5Y neuroblastoma cells. Hence, decursin might be a novel and promising therapeutic option for AD. In addition, our study also provided some new clues to potential target for the intervention and therapy of AD.Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.

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