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

作者全名：Wang, Ziyao; Wang, Bo; Jin, Xin

作者地址：[Wang, Ziyao] Univ South China, Hengyang Med Sch, Dept Ultrasound Med, Affiliated Nanhua Hosp, Hengyang 421001, Hunan, Peoples R China; [Wang, Ziyao] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Ultrasound Med, Hengyang 421001, Hunan, Peoples R China; [Wang, Ziyao] Chongqing Med Univ, Coll Biomed Engn, State Key Lab Ultrasound Med & Engn, Chongqing 400016, Peoples R China; [Wang, Bo] Univ South China, Affiliated Hosp 1, Inst Anesthesiol, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China; [Jin, Xin] Univ South China, Affiliated Nanhua Hosp, Hengyang Med Sch, Dept Anesthesiol, 336 S Dongfeng Rd, Hengyang 421001, Hunan, Peoples R China

通信作者：Jin, X (通讯作者)，Univ South China, Affiliated Nanhua Hosp, Hengyang Med Sch, Dept Anesthesiol, 336 S Dongfeng Rd, Hengyang 421001, Hunan, Peoples R China.

来源：BRAIN RESEARCH BULLETIN

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001257824500001

JCR分区：Q2

影响因子：3.5

年份：2024

卷号：215

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Amentoflavone; Homocysteine; Ferroptosis; Inflammatory response

摘要：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, antiinflammatory, 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 Hcyinduced 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 Hcytreated HT22 cells. In conclusion, these findings suggest that AMF possesses neuroprotection against Hcyinduced injury primarily by inhibiting ferroptosis-mediated inflammation, partly through the activation of SLC7A11/GPX4 axis.

基金机构：Hengyang City 2020 Guiding Project [2020jh042918]; Clinical Medical Technology Innovation Guidance Project of Hunan Province [2021SK51813]

基金资助正文：This study was supported by funding from the Hengyang City 2020 Guiding Project (2020jh042918) and the Clinical Medical Technology Innovation Guidance Project of Hunan Province (2021SK51813) .