Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan.
Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan.
Neurochem Res. 2024 Nov 22;50(1):28. doi: 10.1007/s11064-024-04255-0.
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.
羰基应激是指哺乳动物组织中晚期糖基化终产物（AGEs）的过度积累。这种现象在各种疾病的发病机制中起着重要作用，包括糖尿病、慢性肾衰竭、动脉硬化和中枢神经系统（CNS）疾病。我们之前已经证明，依赖于核因子红细胞 2 相关因子 2（Nrf2）系统的谷胱甘肽浓度的增加提供了针对甲基乙二醛（MGO）诱导的羰基应激的强大细胞保护作用。同时，二甲基富马酸（DMF），因其激活 Nrf2 的作用，最近被批准用于多发性硬化症（MS）的治疗，一种神经退行性疾病。DMF 是复发性缓解型 MS 的一线治疗药物，对其他神经退行性疾病也可能有效。然而，DMF 减轻神经退行性病变的详细机制尚不清楚。本研究探讨了 DMF 对抗羰基活性的影响及其对细胞内羰基蛋白积累的潜在机制。使用甲基乙二醛（MGO），一种葡萄糖代谢物，诱导神经元细胞系发生羰基化。MGO 是一种典型的羰基化合物，它容易与精氨酸和赖氨酸残基反应形成 AGE 修饰的蛋白质。甲基乙二醛衍生的氢咪唑啉酮 1（MG-H1）通常在蛋白质表面形成不带电荷的疏水性残基，这会影响蛋白质的分布并导致错误折叠。我们的研究结果表明，DMF 增加了 SH-SY5Y 细胞中的谷胱甘肽（GSH）、谷胱甘肽半胱氨酸连接酶修饰亚基（GCLM）和核 Nrf2 的水平。重要的是，DMF 预处理可显著减少 MG-H1 修饰蛋白的积累。此外，当抑制 Nrf2 表达和抑制 GSH 合成的限速酶 GCL 时，DMF 的这种作用会减弱。因此，GSH 水平的增加导致 Nrf2 通路的激活，这是 DMF 抑制 MG-H1 修饰蛋白积累能力的关键因素。这项研究首次证明 DMF 具有在神经元细胞中抑制羰基应激的强大作用。因此，未来的研究可能会将 DMF 的应用扩展到其他与羰基应激相关的中枢神经系统疾病，如阿尔茨海默病和帕金森病。
