Nrf2-Independent Anti-Inflammatory Effects of Dimethyl Fumarate: Challenges and Prospects in Developing Electrophilic Nrf2 Activators for Neurodegenerative Diseases
The NF-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is a potential therapeutic target for central nervous system diseases. This review emphasizes the role of oxidative stress and neuroinflammation in neurodegenerative diseases, highlighting the therapeutic potential of Nrf2...
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MDPI AG
2024-12-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/13/12/1527 |
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| author | Yasuhiko Izumi Yutaka Koyama |
| author_facet | Yasuhiko Izumi Yutaka Koyama |
| author_sort | Yasuhiko Izumi |
| collection | DOAJ |
| description | The NF-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is a potential therapeutic target for central nervous system diseases. This review emphasizes the role of oxidative stress and neuroinflammation in neurodegenerative diseases, highlighting the therapeutic potential of Nrf2 activators such as dimethyl fumarate (DMF). DMF, initially administered for treating psoriasis, has demonstrated efficacy in multiple sclerosis and is metabolized to monomethyl fumarate, which may exert significant therapeutic effects. DMF activates the Nrf2-ARE pathway, and recent studies have indicated that its anti-inflammatory effects occur through Nrf2-independent mechanisms. Electrophilic Nrf2 activators, such as DMF, covalently bind to cysteine residues in proteins and modulate their function. We discuss the implications of cysteine residue modifications by DMF, which may cause both therapeutic benefits and potential off-target effects. Furthermore, we propose a chemical proteomics-based drug discovery approach to achieve desired therapeutic effects by selectively covalently modifying cysteines in target proteins. These findings advocate for a broader understanding of the Nrf2-independent mechanisms of electrophilic Nrf2 activators, thereby improving drug discovery strategies that target neurodegenerative diseases while minimizing toxicity. |
| format | Article |
| id | doaj-art-809de53e04534325bb081504f13e8a2d |
| institution | Kabale University |
| issn | 2076-3921 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj-art-809de53e04534325bb081504f13e8a2d2024-12-27T14:06:52ZengMDPI AGAntioxidants2076-39212024-12-011312152710.3390/antiox13121527Nrf2-Independent Anti-Inflammatory Effects of Dimethyl Fumarate: Challenges and Prospects in Developing Electrophilic Nrf2 Activators for Neurodegenerative DiseasesYasuhiko Izumi0Yutaka Koyama1Laboratory of Pharmacology, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, JapanLaboratory of Pharmacology, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, JapanThe NF-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is a potential therapeutic target for central nervous system diseases. This review emphasizes the role of oxidative stress and neuroinflammation in neurodegenerative diseases, highlighting the therapeutic potential of Nrf2 activators such as dimethyl fumarate (DMF). DMF, initially administered for treating psoriasis, has demonstrated efficacy in multiple sclerosis and is metabolized to monomethyl fumarate, which may exert significant therapeutic effects. DMF activates the Nrf2-ARE pathway, and recent studies have indicated that its anti-inflammatory effects occur through Nrf2-independent mechanisms. Electrophilic Nrf2 activators, such as DMF, covalently bind to cysteine residues in proteins and modulate their function. We discuss the implications of cysteine residue modifications by DMF, which may cause both therapeutic benefits and potential off-target effects. Furthermore, we propose a chemical proteomics-based drug discovery approach to achieve desired therapeutic effects by selectively covalently modifying cysteines in target proteins. These findings advocate for a broader understanding of the Nrf2-independent mechanisms of electrophilic Nrf2 activators, thereby improving drug discovery strategies that target neurodegenerative diseases while minimizing toxicity.https://www.mdpi.com/2076-3921/13/12/1527electrophilic Nrf2 activatorsantioxidant effectanti-inflammatory effectdimethyl fumaratemonomethyl fumarate |
| spellingShingle | Yasuhiko Izumi Yutaka Koyama Nrf2-Independent Anti-Inflammatory Effects of Dimethyl Fumarate: Challenges and Prospects in Developing Electrophilic Nrf2 Activators for Neurodegenerative Diseases Antioxidants electrophilic Nrf2 activators antioxidant effect anti-inflammatory effect dimethyl fumarate monomethyl fumarate |
| title | Nrf2-Independent Anti-Inflammatory Effects of Dimethyl Fumarate: Challenges and Prospects in Developing Electrophilic Nrf2 Activators for Neurodegenerative Diseases |
| title_full | Nrf2-Independent Anti-Inflammatory Effects of Dimethyl Fumarate: Challenges and Prospects in Developing Electrophilic Nrf2 Activators for Neurodegenerative Diseases |
| title_fullStr | Nrf2-Independent Anti-Inflammatory Effects of Dimethyl Fumarate: Challenges and Prospects in Developing Electrophilic Nrf2 Activators for Neurodegenerative Diseases |
| title_full_unstemmed | Nrf2-Independent Anti-Inflammatory Effects of Dimethyl Fumarate: Challenges and Prospects in Developing Electrophilic Nrf2 Activators for Neurodegenerative Diseases |
| title_short | Nrf2-Independent Anti-Inflammatory Effects of Dimethyl Fumarate: Challenges and Prospects in Developing Electrophilic Nrf2 Activators for Neurodegenerative Diseases |
| title_sort | nrf2 independent anti inflammatory effects of dimethyl fumarate challenges and prospects in developing electrophilic nrf2 activators for neurodegenerative diseases |
| topic | electrophilic Nrf2 activators antioxidant effect anti-inflammatory effect dimethyl fumarate monomethyl fumarate |
| url | https://www.mdpi.com/2076-3921/13/12/1527 |
| work_keys_str_mv | AT yasuhikoizumi nrf2independentantiinflammatoryeffectsofdimethylfumaratechallengesandprospectsindevelopingelectrophilicnrf2activatorsforneurodegenerativediseases AT yutakakoyama nrf2independentantiinflammatoryeffectsofdimethylfumaratechallengesandprospectsindevelopingelectrophilicnrf2activatorsforneurodegenerativediseases |