Dimethyl fumarate accelerates peripheral nerve regeneration via activation of the anti-inflammatory and cytoprotective Nrf2/HO-1 signaling pathway

Excerpt

Peripheral nerves exhibit a remarkable ability to regenerate; however, there is an unmet need to better understand relevant pathways that could support or even accelerate this process. Fumaric acid esters, especially its dimethyl ester (DMF), are an established treatment option for autoimmune diseases [7]. DMF is known to activate the NF-E2-related factor 2 (Nrf2) transcription factor [8] which is ubiquitously and constitutively expressed and primarily localized in the cytoplasm. Its suppressor, Kelch-like ECH-associated protein 1 (Keap1), prevents Nrf2 from entering the nucleus and acts as an adaptor protein for Nrf2 ubiquitinylation. In case of oxidative or electrophilic stress, Nrf2 is released from Keap1 and translocated into the nucleus to induce antioxidant response element (ARE) gene expression [5]. Additionally, Nrf2 has been demonstrated to induce the expression of heme oxygenase 1 (HO-1) [1], a potent cytoprotective and anti-inflammatory enzyme [9, 10]. An emerging body of experimental evidence suggests that DMF, targeting Keap1 and interfering with the Nrf2/Keap1 interaction, indirectly activates Nrf2 by enabling its translocation into the nucleus [3]. The upregulation of HO-1 expression or activation of anti-oxidative mechanisms has been suggested to account for the efficacy of DMF [2, 4, 6, 8]. To date, it remains unclear whether DMF-mediated anti-inflammatory, anti-oxidative or a synergism of both effects may be sufficient to propagate nerve regeneration in a primary mechanical injury model. …