We investigated the anti-inflammatory activities of
argirein and
rhein on inflammatory
edema in rat paw which was caused by complete adjuvant, compared with
ibuprofen. We hypothesized that the adjuvant-induced
inflammation is attributed to upregulation of activating transcript factor 6 (ATF6; a chaperone for endoplasmic reticulum (ER) stress), p66Shc (an adaptive
protein modulating oxidative stress), and
NADPH oxidase subunits p22phox and gp91phox in the inflamed tissues.
Biomarkers were measured in the rat paw in association with monitoring swellings. The primary inflammatory
edema of the injected paw occurred rapidly and sustained over a couple of days, and the secondary
inflammation developed 2 weeks later. The inflammatory
edema was accompanied by upregulation of
cytokines including ATF6, p66Shc, p22phox, gp91phox, and MMP-2 and an increase in ratio of p-Akt/Akt in the afflicted paw. These were suppressed by either
argirein and
rhein or
ibuprofen. These findings indicate that ER stress, upregulated p66Shc, and phosphorylated Akt are actively implicated in the inflammatory zone caused by adjuvant injection. These
biomarkers were causal factors responsible for
inflammation of the afflicted paw and were suppressed by a supermolecule
argirein and
rhein, and the anti-inflammatory activities of the two compounds were comparable to that of
ibuprofen.