Diroximel Fumarate Acts Through Nrf2 to Attenuate Methylglyoxal-Induced Nociception in Mice and Decrease ISR...

Area of Science:

• Neuroscience
• Metabolic Disorders
• Pharmacology

Background:

• Diabetic neuropathic pain is linked to elevated methylglyoxal (MGO) levels.
• MGO, a glycolysis metabolite, induces pain hypersensitivity via integrated stress response (ISR) activation.
• Zucker diabetic fatty rats exhibit enhanced MGO signaling and pain.

Purpose of the Study:

• To investigate if fumarates, specifically diroximel fumarate (DRF), can mitigate MGO-induced pain.
• To explore the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in this process.

Main Methods:

• Administration of DRF to diabetic rats and MGO-treated mice.
• Assessment of pain hypersensitivity, p-eIF2α levels, and nerve fiber density.
• Utilizing Nrf2 knockout mice to confirm Nrf2's necessity.
• In vitro studies with dorsal root ganglia neurons.

Main Results:

• DRF treatment protected against MGO-induced mechanical and cold hypersensitivity.
• DRF reduced MGO-induced p-eIF2α levels and intraepidermal nerve fiber loss.
• Nrf2 is essential for DRF's pain-alleviating effects.
• Monomethyl fumarate, DRF's active metabolite, prevented ISR in neurons.

Conclusions:

• Targeting Nrf2 with DRF is a potential strategy for managing MGO-related pain.
• DRF demonstrates therapeutic potential for diabetic neuropathic pain.