Amentoflavone attenuates homocysteine-induced neuronal ferroptosis-mediated inflammatory response: Involvement of the SLC7A11/GPX4 axis activation

Ziyao Wang; Bo Wang; Xin Jin

Brain Research Bulletin (Sep 2024)

Amentoflavone attenuates homocysteine-induced neuronal ferroptosis-mediated inflammatory response: Involvement of the SLC7A11/GPX4 axis activation

Ziyao Wang,
Bo Wang,
Xin Jin

Affiliations

Ziyao Wang: The Affiliated Nanhua Hospital, Department of Ultrasound Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; The First Affiliated Hospital, Department of Ultrasound Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China
Bo Wang: The First Affiliated Hospital, Institute of Anesthesiology, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China
Xin Jin: The Affiliated Nanhua Hospital, Department of Anesthesiology, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; Correspondence to: The Affiliated Nanhua Hospital, Department of Anesthesiology, Hengyang Medical School, University of South China, No. 336 S Dongfeng Road, Hengyang, Hunan Province 421001, PR China.

Journal volume & issue: Vol. 215
p. 111005

Abstract

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Elevated homocysteine (Hcy) levels, referred to hyperhomocysteinemia, are associated with an increased risk of several neurological disorders. Ferroptosis and inflammation play a vital role in Hcy-induced neuronal dysfunction. Amentoflavone (AMF), an active natural biflavone compound, exhibits antioxidative, anti-inflammatory, and neuroprotective activities. This study aimed to explore the potential effects of AMF on Hcy-induced neuronal injury, with a particular focus on the underlying mechanisms involving ferroptosis and inflammation. We assessed neuronal damage in HT22 cells by measuring cell viability, lactate dehydrogenase (LDH) release, and proliferation rates. Additionally, we evaluated oxidative stress markers including the levels of reactive oxygen species (ROS), MitoSOX, mitochondrial membrane potential (MMP), malondialdehyde (MDA), and glutathione (GSH). Iron metabolism and ferroptosis-related gene expressions (Ptgs2, Tfr1, and Fth1) were quantified. TheSLC7A11/GPX4 axis was also detected. Our results showed that AMF treatment dramatically mitigated Hcy-induced neuronal injury by increasing cell viability, decreasing LDH release, and promoting cell proliferation. AMF treatment also reduced Hcy-induced oxidative stress and lipid peroxidation, as evidenced by reduced ROS, MitoSOX, MMP, and MDA levels, along with an increased GSH content in HT22 cells. In addition, AMF treatment reduced iron content and ferroptosis-related gene mRNA levels. However, Erastin, a ferroptosis inducer, blocked these neuroprotective effects of AMF. Ferroptosis inhibitor Ferrostatin-1 also attenuated Hcy-induced ferroptosis. Moreover, both AMF and Ferrostatin-1 effectively mitigated Hcy-induced inflammation, which was again antagonized by Erastin. Mechanistically, AMF treatment enhanced SLC7A11/GPX4 axis in Hcy-treated HT22 cells. In conclusion, these findings suggest that AMF possesses neuroprotection against Hcy-induced injury primarily by inhibiting ferroptosis-mediated inflammation, partly through the activation of SLC7A11/GPX4 axis.

Published in Brain Research Bulletin

ISSN: 1873-2747 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.sciencedirect.com/journal/brain-research-bulletin

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