Fig. 5.

Prophylactic A-1396076 treatment does not impact inflammation in CAIA mouse model despite elevation of NRF2 dependent genes. Female Balb/cN mice were given an intravenous injection of an arthritogenic cocktail of five monoclonal antibodies to type II collagen on day 0, followed on day 3 by an intraperitoneal injection of LPS. Mice were then monitored daily for disease development from day 3 until the conclusion of the experiment. A-1396076 (3 ​mg/kg BID or 10 ​mg/kg QD) or indomethacin (1.5 ​mg/kg QD) were administered orally beginning on day 0 prior to injection of anti-collagen antibody cocktail (prophylactic). Clinical arthritis was assessed in each paw as Mean Arthritic Score (MAS) according to presence of redness and swelling at one or more sites (1), two or more sites (2), or deformity in the paws and stiffness in the joints (ankylosis) (3). Clinical scores were summed across all four paws and are reported either by day (A) or AUC from day 3–14 (B) (n ​= ​12; one experiment). (C) Livers (n ​= ​5 per group) were excised at study termination and were used to evaluate the induction of NRF2 dependent genes using duplicate technical replicates by QuantiGene 2.0 assay. NRF2 dependent gene expression levels were upregulated in the liver of mice that received A-1396076 compared to vehicle controls. ∗ ​= ​p ​< ​0.05; ∗∗ ​= ​p ​< ​0.01; ∗∗∗ ​= ​p ​< ​0.001 vs vehicle by one-way ANOVA with Dunnett’s post-test. All data is expressed at mean ​± ​SEM.