Diroximel fumarate acts through Nrf2 to attenuate methylglyoxal-induced nociception in mice and decrease ISR activation in DRG neurons

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 (ZDF) rats have enhanced MGO signaling, engage the 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 (IENF) density. Using Nrf2-knockout mice we demonstrate that Nrf2 is necessary for the anti-nociceptive effects of DRF. Co-treatment of MGO (1µM) with monomethyl fumarate (MMF) (10, 20, 50 µM), the active metabolite of DRF, prevented the ISR in both mouse and human DRG neurons. Our data show that targeting Nrf2 with DRF is a strategy to potentially alleviate pain associated with elevated MGO levels.