2. Academic Validation
  3. Ellagic acid ameliorates arsenic-induced neuronal ferroptosis and cognitive impairment via Nrf2/GPX4 signaling pathway

Ellagic acid ameliorates arsenic-induced neuronal ferroptosis and cognitive impairment via Nrf2/GPX4 signaling pathway

  • Ecotoxicol Environ Saf. 2024 Aug 10:283:116833. doi: 10.1016/j.ecoenv.2024.116833.
Xiyue Yang 1,  Fang Chu 1,  Zhe Jiao 1,  Hao Yu 1,  Wenjing Yang 1,  Yang Li 2,  Chunqing Lu 1,  Hao Ma 1,  Sheng Wang 1,  Zhipeng Liu 1,  Shaoxiao Qin 1,  Hongna Sun 3
Affiliations

Affiliations

  • 1 Institute for Endemic Fluorosis Control, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang 150081, China; NHC Key Laboratory of Etiology and Epidemiology (Harbin Medical University) & Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health & Key Laboratory of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, China.
  • 2 The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Donghu Distinct, Nanchang, Jiangxi 330006, China.
  • 3 Institute for Endemic Fluorosis Control, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang 150081, China; NHC Key Laboratory of Etiology and Epidemiology (Harbin Medical University) & Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health & Key Laboratory of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, China. Electronic address: hrbmushn@hrbmu.edu.cn.
PMID: 39128446 DOI: 10.1016/j.ecoenv.2024.116833
Abstract

Arsenic, a neurotoxic metalloid, poses significant health risks. However, ellagic acid, renowned for its antioxidant properties, has shown potential in neuroprotection. This study aimed to investigate the neuroprotective effects of ellagic acid against arsenic-induced neuronal Ferroptosis and cognitive impairment and elucidate the underlying mechanisms. Using an arsenic-exposed Wistar rat model and an arsenic-induced HT22 cells model, we assessed cognitive ability, measured serum and brain arsenic levels, and evaluated pathological damage through histological analysis and transmission electron microscopy. Additionally, we examined oxidative stress and iron ion levels using GSH, MDA, ROS and tissue iron biochemical kits, and analyzed the expression of ferroptosis-related markers using western blot and qRT-PCR. Our results revealed that arsenic exposure increased both serum and brain arsenic levels, resulting in hippocampal pathological damage and subsequent decline in learning and memory abilities. Arsenic-induced neuronal Ferroptosis was mediated by the inhibition of the xCT/GSH/GPX4/Nrf2 signaling axis and disruption of iron metabolism. Notably, ellagic acid intervention effectively reduced serum and brain arsenic levels, ameliorated neuronal damage, and improved oxidative stress, Ferroptosis, and cognitive impairment. These beneficial effects were associated with the activation of the Nrf2/Keap1 signaling pathway, upregulation of GPX4 expression, and enhanced iron ion excretion. In conclusion, ellagic acid demonstrates promising neuroprotective effects against arsenic-induced neurotoxicity by mitigating neuronal Ferroptosis and cognitive impairment.

Keywords

Arsenic; Ellagic acid; Ferroptosis; Glutathione peroxidase 4; Hippocampal neuron; Nuclear factor E2-related factor 2.

Figures
Products