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.
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