Diroximel fumarate confers neuroprotection via reduced Th1 responses and induction of the anti-oxidative Nrf2 pathway in experimental neuroinflammation

Abstract

Inflammation and oxidative stress contribute significantly to tissue damage in multiple sclerosis. Fumaric acid esters such as Dimethyl fumarate and Diroximel fumarate (DRF) exhibit immunomodulatory and antioxidative properties, although their mechanisms remain incompletely understood. This study investigated the immunomodulatory and antioxidative mechanisms of fumaric acid esters, with a focus on DRF and its ability to confer neuroprotection in autoimmune neuroinflammation. The MOG-experimental autoimmune encephalomyelitis (EAE) mouse model was employed and DRF was administered orally. In addition to clinical scoring of EAE severity, histological analyses were performed to assess inflammatory infiltration, demyelination, and axonal density. Immune responses were examined via immunophenotyping and cytokine measurements, and mRNA expression was analyzed to evaluate Nrf2 pathway activation. DRF treatment markedly ameliorated clinical EAE severity, reduced spinal cord infiltration of T cells—particularly Th1 cells—and promoted myelin and axonal preservation. Peripheral immune cells from DRF-treated mice produced lower levels of IFN-γ and IL-17A, while Nrf2-dependent antioxidative genes were upregulated in CNS tissue. Our results demonstrate neuroprotective, immunomodulatory, and antioxidative effects of DRF, supporting its role as beneficial modulator in neuroinflammation.