Diacerein ameliorates acute urarthritis in rats through the Nrf-2/HO-1 and NF-κB pathways

Urarthritis is an inflammatory disorder triggered by monosodium urate (MSU) crystal deposition, and its pathogenesis involves interaction between oxidative stress (OS) and inflammation. Diacerein, an agent endowed with anti-inflammatory and antioxidant properties, has not yet been fully characterized in acute urarthritis. This study was designed to evaluate the therapeutic efficacy of diacerein in acute urarthritis and to elucidate its regulatory effects on the Nrf-2/HO-1 and NF-κB pathways.

The Wistar rat model of acute urarthritis was established, and 50 rats were randomly divided into 5 groups (10 rats per group): normal control group (AG, gavage with 0.5% sodium carboxymethyl cellulose), model group (BG, gavage with 0.5% sodium carboxymethyl cellulose), low-dose diacerein group (CG, gavage with 50 mg/kg diacerein), medium-dose diacerein group (DG, gavage with 100 mg/kg diacerein), high-dose diacerein group (EG, gavage with 200 mg/kg diacerein), and positive control group (FG, gavage with 5 mg/kg indomethacin). After continuous administration for 7 days, the ankle joint swelling degree, mechanical pain threshold, serum inflammatory factors (IL-1β, TNF-α, IL-6) levels, renal function indicators (blood urea nitrogen BUN, creatinine Cr, uric acid UA, kidney index) of rats in each group were detected, and the expression of Nrf-2/HO-1 and NF-κB pathway-related proteins in ankle joint synovial tissue was analyzed by Western blot.

Compared with the BG, diacerein groups and the FG significantly reduced the percentage of ankle swelling (P < 0.001) and increased the mechanical pain threshold (P < 0.001): At 24 h after modeling, there was no statistical difference in the swelling percentage between the EG and the FG (P > 0.05); At 7 days after modeling, the mechanical pain threshold in the EG was similar to that in the FG (P > 0.05). The serum levels of IL-1β, TNF-α, and IL-6 in the intervention groups were reduced in a dose-dependent manner (P < 0.001), and the inhibition rate of IL-1β in the EG exceeded 73%, which was comparable to that in the FG (P > 0.05); Renal function indicators were significantly improved (P < 0.001), and there was no significant difference in the UA level between the EG and the FG (P > 0.05). Mechanistically, diacerein dose-dependently up-regulated the expression of Nrf-2 and HO-1 proteins (P < 0.001) and down-regulated the expression of NF-κB p65 and p-IκBα proteins (P < 0.001); The FG only significantly down-regulated the expression of NF-κB p65 and p-IκBα proteins (P < 0.001), with no significant effect on the expression of Nrf-2 and HO-1 proteins (P > 0.05). The ratios of Nrf-2/GAPDH and HO-1/GAPDH in the EG were significantly higher than those in the FG (P < 0.001).

The anti-inflammatory, analgesic, and renal protective effects of high-dose diacerein are comparable to those of indomethacin, and its oral administration is convenient, which provides experimental references for the subsequent clinical transformation research of diacerein in acute urarthritis and the development of multi-target anti-gout drugs.