The protective effect of N-acetylcysteine on hippocampal ferroptosis in an experimental obesity model

Abstract

Ferroptosis is a non-apoptotic cell death closely related to a metabolic pathway involving iron overload, imbalanced glutathione metabolism, oxidative stress and lipid peroxidation damage. Obesity is closely associated with these imbalances. In this study, we aimed to investigate the effect of hippocampal ferroptosis in an obesity model and the potential role of N-acetylcysteine (NAC) against ferroptosis. A high-fat (60%) dietary pattern was used to establish an obesity model for 15 weeks. NAC was administered to NAC and Obese+NAC (ObNAC) groups by oral gavage at a dose of 150 mg/kg for 3 weeks. Glutathione peroxidase 4 (GPX4) and the cystine transporter solute carrier family 7- member 11 (SLC7A11) expression levels were investigated immunohistochemically to detect ferroptosis in hippocampal tissues. In the statistical analysis, H-scores of GPX4 and SLC7A11 in the hippocampus sections of the Ob group were significantly lower than in the control, NAC and ObNAC groups (p<0.01). On the other hand, NAC treatment significantly attenuated hippocampal ferroptosis by maintaining both GPX4 and SLC7A11 expression levels in the ObNAC group. These findings imply that ferroptosis may be essential in the hippocampus, an area of the brain critical for memory, learning, and emotional reactions in obese individuals. In addition, NAC, a promoter of GSH biosynthesis, may attenuate hippocampal ferroptosis in obesity by inhibiting the downregulation of GPX4 and SLC7A11 expression signaling.

Keywords

• ferroptosis
• GPX4
• hippocampus
• brain

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