The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice

Abstract

The transcription factor NF-E2-related factor 2 (Nrf2) is a key regulator of cellular defense mechanisms against oxidative stress. Multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system, is characterized by progressive demyelination and neurodegeneration induced by inflammation and oxidative stress. The induction of Nrf2 signaling has been shown to inhibit disease development and progression in the experimental autoimmune encephalomyelitis (EAE) model of MS in mice. In the present study, we performed a high-throughput screening assay using a chimeric construct of the N-terminal portion of Nrf2 fused to LacZ. Using this approach, we identified the novel Nrf2 inducer TFM-735. Using human primary cell profiling systems, we found that TFM-735 inhibited T cell proliferation and exerted immuno-modulatory effects by inhibiting the production of IL-6 and IL-17. TFM-735 also inhibited IL-17 secretion from human peripheral blood mononuclear cells stimulated with anti-CD3 and anti-CD28. In EAE mice treated with TFM-735, the expression of the Nrf2 target gene Nqo1 increased in the brain and spleen, disease severity was ameliorated, and plasma IL-17 levels decreased. Furthermore, TFM-735 inhibited luciferase activity in Wim-6 transgenic EAE mice expressing the human interleukin 6-luciferase (hIL6-BAC-Luc) reporter. Therefore, these findings indicate that TFM-735 is a potent Nrf2 inducer that inhibits inflammatory cytokine production and disease progression in mice with EAE and that TFM-735 is a promising therapeutic agent for MS.

Keywords: Dimethyl fumarate (PubChem CID: 637568); EAE; FTY720 (PubChem CID: 107969); IL-17; IL-6; Nrf2.