ArticleDiabetes2025
Diroximel Fumarate Acts Through Nrf2 to Attenuate Methylglyoxal-Induced Nociception in Mice and Decrease ISR Activation in DRG Neurons.
Article in Diabetes, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Complex Contributions of Methylglyoxal to Pain, Axon Degeneration, and Diabetic Peripheral Neuropathy.Journal of neurochemistry · 2026Review
- Progressive neurodegeneration in human dorsal root ganglion from diabetes to painful neuropathy.bioRxiv : the preprint server for biology · 2026Article
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- Eukaryotic initiation factor 3d Regulates Context-Dependent Pain Hypersensitivity Through the Integrated Stress Response.bioRxiv : the preprint server for biology · 2025Article
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- Fumarate-based drugs protect against neuroinflammation via upregulation of anti-ferroptotic pathways.Journal of neuroinflammation · 2025Article
- Long-lasting and fast methylglyoxal-scavenging peptide CycK(Myr)RPain reports · 2025Article
- Spatial transcriptomic profiling of human paravertebral sympathetic chain ganglia reveals diabetes-induced neuroplasticity.bioRxiv : the preprint server for biology · 2025Article
- Eukaryotic initiation factor 3d regulates context-dependent pain hypersensitivity through the integrated stress response.Neurobiology of pain (Cambridge, Mass.)Article
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Abstract
Diabetic neuropathic pain is associated with elevated plasma levels of methylglyoxal (MGO). MGO is a metabolite of glycolysis that causes pain hypersensitivity in mice by stimulating the phosphorylation of eukaryotic initiation factor 2α (p-eIF2α) and subsequently activating the integrated stress response (ISR). We first established that Zucker diabetic fatty rats have enhanced MGO signaling, engage ISR, and develop pain hypersensitivity. Since nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of antioxidant proteins that neutralize MGO, we hypothesized that fumarates, like diroximel fumarate (DRF), will stimulate Nrf2 signaling, and prevent MGO-induced ISR and pain hypersensitivity. DRF (100 mg/kg) treated animals were protected from developing MGO (20 ng) induced mechanical and cold hypersensitivity. Mechanistically, DRF treatment protected against MGO-induced increase in p-eIF2α levels in the sciatic nerve and reduced loss of intraepidermal nerve fiber density. Using Nrf2 knockout mice, we demonstrate that Nrf2 is necessary for the antinociceptive effects of DRF. Cotreatment of MGO (1 µmol/L) with monomethyl fumarate (10, 20, and 50 µmol/L), the active metabolite of DRF, prevented ISR in both mouse and human dorsal root ganglia neurons. Our data show that targeting Nrf2 with DRF is a strategy to potentially alleviate pain associated with elevated MGO levels. ARTICLE HIGHLIGHTS:
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