Berberine ameliorates iron levels and ferroptosis in the brain of 3 × Tg-AD mice

Xinlu Li; Jianfeng Chen; Wennuo Feng; Chao Wang; Minyu Chen; Yifan Li; Jinghong Chen; Xinwei Liu; Qiong Liu; Jing Tian

doi:10.1016/j.phymed.2023.154962

Berberine ameliorates iron levels and ferroptosis in the brain of 3 × Tg-AD mice

Phytomedicine. 2023 Sep:118:154962. doi: 10.1016/j.phymed.2023.154962. Epub 2023 Jul 17.

Authors

Xinlu Li¹, Jianfeng Chen², Wennuo Feng³, Chao Wang⁴, Minyu Chen², Yifan Li², Jinghong Chen², Xinwei Liu², Qiong Liu¹, Jing Tian⁵

Affiliations

¹ Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong 518055, China; Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China.
² Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong 518055, China.
³ Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong 518055, China; Shenzhen Bay Laboratory, Shenzhen, Guangdong 518055, China.
⁴ Chemical Analysis & Physical Testing Institute, Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong 518055, China.
⁵ Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong 518055, China. Electronic address: jtian@szu.edu.cn.

PMID: 37506403
DOI: 10.1016/j.phymed.2023.154962

Abstract

Background: Berberine (BBR) is a natural alkaloid extracted from the herb Coptis chinensis. This compound has the ability to penetrate the blood-brain barrier (BBB) and exhibit neuroprotective value in the treatment of Alzheimer's disease (AD). AD is a neurodegenerative disease characterized by β-amyloid (Aβ) deposition, hyperphosphorylated tau and other characters. Iron accumulation and ferroptosis were also detected in AD brain, which can result in neuronal damage. However, it is still unclear whether BBR can suppress ferroptosis in AD and alleviate its underlying pathology.

Purpose: This study investigated whether BBR may affect ferroptosis and related signaling pathways in triple transgenic AD (3 × Tg-AD) mice.

Methods: Four-month-old 3 × Tg-AD mice received oral administration of BBR at a dose of 50 mg/kg for 7.5 months. Cognitive function and anxiety levels in mice were assessed using the morris water maze test, open field test, and novel object recognition test. Western blot, immunohistochemistry, and ICP-MS were employed to assess the pathology of AD, brain iron metabolism, and ferroptosis signaling pathways. Transmission electron microscopy was used to detect mitochondrial changes. The synergistic effects of BBR combined with Nrf2 were investigated using molecular docking programs and surface plasmon resonance technology. Co-inmunoprecipitation assay was used to examine the effect of BBR on the binding ability of Nrf2 and Keap1.

Results: The results indicated that chronic treatment of BBR mitigated cognitive disorders in 3 × Tg-AD model mice. Reductions in Aβ plaque, hyperphosphorylated tau protein, neuronal loss, and ferroptosis in the brains of 3 × Tg-AD mice suggested that BBR could alleviate brain injury. In addition, BBR treatment attenuated ferroptosis, as evidenced by decreased levels of iron, MDA, and ROS, while enhancing SOD, GSH, GPX4, and SLC7A11. Consistent with the in vivo assay, BBR inhibited RSL3-induced ferroptosis in N2a-sw cells. BBR increased the expression levels of GPX4, FPN1 and SLC7A11 by regulating Nrf2 transcription levels, thereby inhibiting ferroptosis. Molecular docking programs and surface plasmon resonance technology demonstrated the direct combination of BBR with Nrf2. Co-inmunoprecipitation analysis showed that BBR inhibited the interaction between Keap1 and Nrf2.

Conclusion: For the first time, these results showed that BBR could inhibit iron levels and ferroptosis in the brains of 3 × Tg-AD model mice and partially protect against RSL3-induced ferroptosis via the activation of Nrf2 signaling.

Keywords: Alzheimer's disease; Berberine; Ferroptosis; Iron levels.

MeSH terms

Alzheimer Disease* / metabolism
Animals
Berberine* / pharmacology
Berberine* / therapeutic use
Brain
Ferroptosis*
Iron / metabolism
Kelch-Like ECH-Associated Protein 1 / metabolism
Mice
Mice, Transgenic
Molecular Docking Simulation
NF-E2-Related Factor 2 / metabolism
Neurodegenerative Diseases* / drug therapy

Substances

Berberine
Kelch-Like ECH-Associated Protein 1
NF-E2-Related Factor 2
Iron