title: A novel aza-anthrapyrazole blocks the progression of experimental autoimmune encephalomyelitis after the priming of autoimmunity.
abstract: Mitoxantrone is one of the few FDA-approved drugs available to treat rapidly progressing forms of multiple sclerosis; however, its utilization is compromised by a cardiotoxic potential and the risk of mitoxantrone-induced leukemia. BBR3378, a novel aza-anthrapyrazole, is structurally similar to mitoxantrone, but lacks the ring hydroxyls that may contribute to cardiotoxicity. Here, we investigated the therapeutic activity of BBR3378 in a C57BL/6 mouse model of multiple sclerosis. Mice given BBR3378, before or after the priming and expansion of MOG-specific responses, were protected from ascending paralysis. Strikingly, two doses of BBR3378 given a week after EAE induction were sufficient to provide significant protection from clinical symptoms and reduce MOG-specific proinflammatory T cell cytokine production, and serum IgG responses. Furthermore, while mitoxantrone is associated with persistent lymphopenia and cardiotoxicity, no such outcomes were detected in BBR3378-treated mice. Our findings show that BBR3378 can ameliorate encephalitogenic mechanisms in EAE and antagonize underlying autoimmune mechanisms.
authors.affiliation: Department of Pharmacology, University of Toledo Medical Center, Toledo, OH 43614, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Kiraly
authors.forename: Boyd
authors.initials: B
authors.lastname: Koffman
authors.forename: Miles
authors.initials: M
authors.lastname: Hacker
authors.forename: William
authors.initials: W
authors.lastname: Gunning
authors.forename: Sarah
authors.initials: S
authors.lastname: Rasche
authors.forename: Anthony
authors.initials: A
authors.lastname: Quinn
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D007074:Immunoglobulin G / Q000097:blood / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008942:Mitoxantrone / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D009185:Myelin Proteins / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: C569470:BBR3378; D016207:Cytokines; D007074:Immunoglobulin G; C571327:Mog protein, mouse; D009185:Myelin Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D008942:Mitoxantrone