Gastrodin inhibits ferroptosis to alleviate hypoxic-ischemic brain damage in neonatal mice by activating GPX4/SLC7A11/FTH1 signaling.
10.12122/j.issn.1673-4254.2025.10.03
- Author:
Tao GUO
1
;
Bolin CHEN
1
;
Jinsha SHI
1
;
Xianfeng KUANG
1
;
Tengyue YU
1
;
Song WEI
1
;
Xiong LIU
2
;
Rong XIAO
1
;
Juanjuan LI
1
Author Information
1. Department of Human Anatomy & Histology and Embryology, School of Basic Medical Sciences, Kunming Medical University, Kunming 650500, China.
2. Department of Anatomy, School of Basic Medical Sciences, Kunming University of Science and Technology, Kunming 650500, China.
- Publication Type:Journal Article
- Keywords:
GPX4/SLC7A11/FTH1;
ferroptosis;
gastrodin;
hypoxic-ischemic brain damage;
neurons;
oxygen-glucose deprivation
- MeSH:
Animals;
Ferroptosis/drug effects*;
Hypoxia-Ischemia, Brain/drug therapy*;
Mice;
Mice, Inbred C57BL;
Signal Transduction/drug effects*;
Phospholipid Hydroperoxide Glutathione Peroxidase;
Glucosides/pharmacology*;
Animals, Newborn;
Benzyl Alcohols/pharmacology*;
Amino Acid Transport System y+/metabolism*
- From:
Journal of Southern Medical University
2025;45(10):2071-2081
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVES:To evaluate the therapeutic effect of gastrodin against hypoxic-ischemic brain damage (HIBD) in neonatal mice and explore the role of GPX4/SLC7A11/FTH1 signaling in mediating its effect.
METHODS:Twenty-four 9- to 11-day-old C57BL/6J mice were randomized equally into 4 groups for sham operation, HIBD modeling by right common carotid artery ligation and subsequent exposure to hypoxia for 1 h, or gastrodin treatment at 100 or 200 mg/kg before and at 1 and 2 days after modeling. The mice then underwent neurological assessment (Zea-Longa scores), and the cerebral cortical penumbra tissue were collected for HE and Nissl staining, detection of ferroptosis biomarkers and protein expressions of GPX4, SLC7A11, and FTH1 with Western blotting and immunofluorescence co-localization, and observation of mitochondrial ultrastructure with electron microscopy. In cultured HT22 neuronal cells with oxygen-glucose deprivation (OGD) for 2 h, the effects of pretreatments with 0.5 mmol/L gastrodin, 10 μmol/L RSL3 (a GPX4 inhibitor), alone or in combination, were analyzed on expressions of ferroptosis-related proteins, cellular Fe²⁺, ROS, lipid peroxidation, MDA, and GSH levels, mitochondrial membrane potential (JC-1), and cell viability.
RESULTS:Gastrodin treatment at the two doses both significantly ameliorated HIBD and neurological deficits of the mice, reduced mitochondrial damage and Fe²⁺, MDA and ROS levels, increased GSH level, and upregulated GPX4, SLC7A11, and FTH1 protein expressions. In HT22 cells, gastrodin pretreatment obviously attenuated OGD-induced ferroptosis and improved cell viability and mitochondrial function. Co-treatment with RSL3 potently abrogated the inhibitory effects of gastrodin on Fe²⁺, ROS, BODIPY-C11, and MDA levels and attenuated its protective effects on GSH level, cell viability, and mitochondrial membrane potential.
CONCLUSIONS:Gastrodin provides neuroprotective effects in neonatal mice with HIBD by suppressing neuronal ferroptosis via upregulating the GPX4/SLC7A11/FTH1 signaling pathway.
