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
- Methylglyoxal (MGO) induces mechanical and cold hypersensitivity in mice that is prevented with daily treatment with diroximel fumarate (DRF).
- DRF protects against MGO-induced integrated stress response activation in the sciatic nerve and loss of intraepidermal nerve fibers.
- DRF treatment does not protect Nrf2 knockout mice from developing pain hypersensitivity, suggesting that Nrf2 is necessary for DRF’s antinociceptive effects.
- Monomethyl fumarate, the active metabolite of DRF, prevents MGO-induced increase in p-eIF2α levels in mouse and human dorsal root ganglia neurons in vitro.
- Nrf2 activators, like the Food and Drug Administration–approved DRF, could be evaluated in clinical trials for diabetic neuropathic pain.
