Dimethyl Fumarate Reduces Methylglyoxal-derived Carbonyl Stress Through Nrf2/GSH Activation in SH-SY5Y Cells

Carbonyl stress refers to the excessive accumulation of advanced glycation end products (AGEs) in mammalian tissues. This phenomenon plays a significant role in the pathogenesis of various diseases, including diabetes, chronic renal failure, arteriosclerosis, and central nervous system (CNS) disorders. We have previously demonstrated that an increase in glutathione concentration, dependent on the nuclear factor erythroid 2-related factor 2 (Nrf2) system, provides a potent cytoprotective effect against Methylglyoxal (MGO)-induced carbonyl stress. Meanwhile, dimethyl fumarate (DMF), known for its Nrf2-activating effects, was recently approved as a treatment for multiple sclerosis (MS), a neurodegenerative disease. DMF is a first line therapy for relapsing-remitting MS and may also be effective for other neurodegenerative conditions. However, the detailed mechanisms by which DMF mitigates neurodegenerative pathologies remain unclear. This study investigates the impact of DMF on anticarbonyl activity and its underlying mechanism focusing on the accumulation of carbonyl protein in the cell. MGO, a glucose metabolite, was used to induce carbonylation in the neuronal cell line. MGO is a typical carbonyl compound that readily reacts with arginine and lysine residues to form AGE-modified proteins. Methylglyoxal-derived hydroimidazolone 1 (MG-H1) often forms uncharged, hydrophobic residues on the protein surface, which can affect protein distribution and lead to misfolding. Our findings indicate that DMF increases levels of glutathione (GSH), glutamate cysteine ligase modifier subunit (GCLM), and nuclear Nrf2 in SH-SY5Y cells. Importantly, DMF pretreatment significantly reduced the accumulation of MG-H1-modified proteins. Furthermore, this effect of DMF was diminished when Nrf2 expression was suppressed and when GCL, a rate-limiting enzyme in GSH synthesis, was inhibited. Thus, the increase in GSH levels, leading to the activation of the Nrf2 pathway, a key factor in DMF's ability to suppress the accumulation of MG-H1-modified proteins. This study is the first to demonstrate that DMF possesses strong anticarbonyl stress activity in neuronal cells. Therefore, future research may extend the application of DMF to other CNS diseases associated with carbonyl stress, such as Alzheimer's and Parkinson's disease.