title: Triterpenoid modulation of IL-17 and Nrf-2 expression ameliorates neuroinflammation and promotes remyelination in autoimmune encephalomyelitis.
abstract: Inflammatory cytokines and endogenous anti-oxidants are variables affecting disease progression in multiple sclerosis (MS). Here we demonstrate the dual capacity of triterpenoids to simultaneously repress production of IL-17 and other pro-inflammatory mediators while exerting neuroprotective effects directly through Nrf2-dependent induction of anti-oxidant genes. Derivatives of the natural triterpene oleanolic acid, namely CDDO-trifluoroethyl-amide (CDDO-TFEA), completely suppressed disease in a murine model of MS, experimental autoimmune encephalomyelitis (EAE), by inhibiting Th1 and Th17 mRNA and cytokine production. Encephalitogenic T cells recovered from treated mice were hypo-responsive to myelin antigen and failed to adoptively transfer the disease. Microarray analyses showed significant suppression of pro-inflammatory transcripts with concomitant induction of anti-inflammatory genes including Ptgds and Hsd11b1. Finally, triterpenoids induced oligodendrocyte maturation in vitro and enhanced myelin repair in an LPC-induced non-inflammatory model of demyelination in vivo. These results demonstrate the unique potential of triterpenoid derivatives for the treatment of neuroinflammatory disorders such as MS.
authors.affiliation: Department of Pediatrics/Division of Pediatric Hematology-Oncology, University Hospitals Case Medical Center and The Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pareek
authors.forename: Abdelmadjid
authors.initials: A
authors.lastname: Belkadi
authors.forename: Sashi
authors.initials: S
authors.lastname: Kesavapany
authors.forename: Anita
authors.initials: A
authors.lastname: Zaremba
authors.forename: Sook L
authors.initials: SL
authors.lastname: Loh
authors.forename: Lianhua
authors.initials: L
authors.lastname: Bai
authors.forename: Mark L
authors.initials: ML
authors.lastname: Cohen
authors.forename: Colin
authors.initials: C
authors.lastname: Meyer
authors.forename: Karen T
authors.initials: KT
authors.lastname: Liby
authors.forename: Robert H
authors.initials: RH
authors.lastname: Miller
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.forename: John J
authors.initials: JJ
authors.lastname: Letterio
mesh_terms: D000818:Animals; D005260:Female; D008297:Male; D051379:Mice; D051381:Rats; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007249:Inflammation; D020381:Interleukin-17 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D009836:Oligodendroglia / Q000166:cytology; D020411:Oligonucleotide Array Sequence Analysis; D017208:Rats, Wistar; D012333:RNA, Messenger / Q000378:metabolism; D018417:Th1 Cells; D014315:Triterpenes / Q000494:pharmacology
chemical_list: C568680:(2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) trifluoroethylamide; D016207:Cytokines; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C491523:Hmox1 protein, rat; D020381:Interleukin-17; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D052247:Nitric Oxide Synthase Type II; D009828:Oleanolic Acid; D012333:RNA, Messenger; D014315:Triterpenes; C495637:Nfe2l2 protein, rat