Department of Animal and Human Physiology, Faculty of Biology, University of Gdańsk, Ul. Wita Stwosza 59, 80-308, Gdańsk, Poland.
Eur J Pharmacol. 2022 Jul 5;926:175025. doi: 10.1016/j.ejphar.2022.175025. Epub 2022 May 13.
Dimethyl fumarate (DMF) is an antioxidative and anti-inflammatory drug approved for treatment of multiple sclerosis and psoriasis; however, beneficial effects of DMF have also been found in other inflammatory diseases and cancers. DMF is a prodrug that is immediately hydrolysed to monomethyl fumarate (MMF) in vivo. Both fumarates activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, and Nrf2 is a key transcription factor of the antioxidant response. The immunosuppressive and anti-inflammatory actions of DMF occur through several mechanisms: via inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and by downregulation of aerobic glycolysis and pyroptosis in activated myeloid and lymphoid cells. MMF is also an agonist of hydroxycarboxylic acid receptor 2 (HCAR2). Differences in the strength of effects and mechanisms of action of both fumarates are discussed. The aim of this review was to analyse and compare the neuroprotective, antioxidative and anti-inflammatory effects of DMF and its active metabolite, MMF, in cellular (in vitro) and animal models of neurodegenerative diseases (NDs), other than multiple sclerosis. There are more than twenty studies that currently represent this field. Most of the studies are concerned with cellular or animal models of Alzheimer's disease (AD) and Parkinson's disease (PD), one utilized a mouse model of Huntington's disease (HD) and one clinical trial was carried out with amyotrophic lateral sclerosis (ALS) patients. The discrepancies in the results of the various studies are discussed, and issues requiring further research have been identified.
富马酸二甲酯 (DMF) 是一种抗氧化和抗炎药物，已被批准用于治疗多发性硬化症和银屑病；然而，DMF 在其他炎症性疾病和癌症中也显示出有益的效果。DMF 是一种前体药物，在体内立即水解为单甲基富马酸 (MMF)。两种富马酸盐均可激活核因子 (红系衍生 2)-样 2 (Nrf2) 途径，而 Nrf2 是抗氧化反应的关键转录因子。DMF 的免疫抑制和抗炎作用通过多种机制发生：通过抑制核因子 kappa-轻链增强子的激活 B 细胞 (NF-κB) 途径和通过下调活化的髓样和淋巴样细胞中的需氧糖酵解和细胞焦亡。MMF 也是羟基羧酸受体 2 (HCAR2) 的激动剂。两种富马酸盐的作用强度和作用机制的差异正在讨论中。本综述的目的是分析和比较 DMF 及其活性代谢物 MMF 在除多发性硬化症以外的神经退行性疾病 (ND) 的细胞 (体外) 和动物模型中的神经保护、抗氧化和抗炎作用。目前有二十多项研究代表了这一领域。大多数研究涉及阿尔茨海默病 (AD) 和帕金森病 (PD) 的细胞或动物模型，一项研究利用亨廷顿病 (HD) 的小鼠模型，一项临床试验针对肌萎缩侧索硬化症 (ALS) 患者进行。讨论了各种研究结果的差异，并确定了需要进一步研究的问题。
