Ferroptosis in the Substantia Nigra Pars Compacta of Mice: Triggering Role of Ultrafine Diesel Exhaust Particles and Mitigation by α-Lipoic Acid

Recent epidemiological and experimental studies have increasingly highlighted the association between environmental pollution, especially ultrafine particulate matter (PM), and the risk of neurodegenerative diseases, such as Parkinson's disease (PD). These previous studies suggest a potential mechanism by which ultrafine PM contributes to neuronal damage through processes, such as iron accumulation and oxidative stress. In this study, we aimed to elucidate the effects of ultrafine PM on ferroptosis, an iron-dependent form of cell death, in the mouse substantia nigra pars compacta (SNc) and to evaluate the protective role of alpha-lipoic acid (ALA). Mice were exposed to ultrafine diesel exhaust particles (ufDEP), a type of ultrafine PM, intranasally and injected ALA intraperitoneally for seven consecutive days. Iron accumulation and lipid peroxidation were significantly increased, and antioxidant capacity was significantly decreased in the SNc after ufDEP exposure, highlighting the deleterious effects of ufDEP on tyrosine hydroxylase (TH)-positive neurons. In contrast, ALA treatment effectively mitigated these effects by reducing iron accumulation, decreasing lipid peroxidation, and restoring antioxidant levels, resulting in the protection of TH-positive neurons from ferroptotic damage. Our results provide evidence that ufDEP can induce ferroptosis in dopaminergic neurons in the SNc, potentially contributing to PD pathogenesis. Furthermore, ALA showed protective effects against ufDEP-induced ferroptotic damage, suggesting its potential as a therapeutic intervention for PD.