Dimethyl fumarate improves nuclear factor erythroid-related factor 2-mediated antioxidant response to ameliorate functional and molecular deficits in experimental diabetic neuropathy.

Objectives: In the present study, we tested the functional/pharmacological significance of dimethyl fumarate (DMF) in streptozotocin-induced diabetic neuropathy (DN) in rats and high glucose-exposed Neuro2a (N2a) cells.

Materials And Methods: To evaluate the pharmacological effects of DMF on diabetic neuropathy, we assessed behavioral and functional parameters of peripheral neuropathy, oxidative stress markers, and target protein expression using immunohistochemistry/immunocytochemistry, and Western blotting in diabetic rats and hyperglycemic N2a cells.

Results: Diabetic rats exhibited hyperalgesia, allodynia, and compromised sensory and motor nerve conduction velocities in comparison to normal rats. Dorsal root ganglias of diabetic rats showed decreased antioxidant levels and increased pro-inflammatory transcription factors such as nuclear factor erythroid-related factor 2 and nuclear factor-kappa B, alongside reduced expression of the heat shock protein (HSP) 90. Administering DMF to diabetic rats for 2 weeks reversed these effects in a dose-dependent manner. We observed significant compromise in mitochondrial function, indicated by reduced mitochondrial membrane potential, increased free radical levels, and compromised mitochondrial complex activities in N2a cells exposed to elevated glucose levels. Conversely, DMF treatment restored mitochondrial function and augmented mitochondrial biogenesis through the upregulation of PGC-1α and improved chaperone activity by increasing the expression of HSP 60 and HSP 70.

Conclusions: Overall, DMF alleviated neurobehavioral deficits in DN rats and enhanced mitochondrial function and chaperone activity under hyperglycemic conditions in both diabetic rats and N2a cells.