title: 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.
authors.affiliation: Discovery Research, Mochida Pharmaceutical Co., Ltd., 722 Uenohara, Jimba, Gotemba 412-8524, Japan; Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. Electronic address: chika.higashi@mochida.co.jp.
authors.forename: Chika
authors.initials: C
authors.lastname: Higashi
authors.affiliation: Discovery Research, Mochida Pharmaceutical Co., Ltd., 722 Uenohara, Jimba, Gotemba 412-8524, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Kawaji
authors.affiliation: Discovery Research, Mochida Pharmaceutical Co., Ltd., 722 Uenohara, Jimba, Gotemba 412-8524, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Tsuda
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Saito
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yagishita
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. Electronic address: uruno@med.tohoku.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Uruno
authors.affiliation: Discovery Research, Mochida Pharmaceutical Co., Ltd., 722 Uenohara, Jimba, Gotemba 412-8524, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Discovery Research, Mochida Pharmaceutical Co., Ltd., 722 Uenohara, Jimba, Gotemba 412-8524, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Discovery Research, Mochida Pharmaceutical Co., Ltd., 722 Uenohara, Jimba, Gotemba 412-8524, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Furusako
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. Electronic address: masiyamamoto@med.tohoku.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D020381:Interleukin-17; D015850:Interleukin-6; D051267:NF-E2-Related Factor 2; D011720:Pyrazoles; C000617977:TFM-735; D013844:Thiazoles
keywords: Dimethyl fumarate (PubChem CID: 637568); EAE; FTY720 (PubChem CID: 107969); IL-17; IL-6; Nrf2