Praziquantel ameliorates leflunomide-induced nephrotoxicity in mice: a novel therapeutic approach targeting TGF-β/Smad/Wnt/β-catenin/NF-κB/PPAR-γ signaling and Nrf-2.

Leflunomide (LF), an essential immunomodulator for autoimmune disorders, poses a risk of nephrotoxicity. This work was designed to examine the possible mechanisms of LF nephrotoxicity and to investigate the potential protective role of praziquantel (PZQ), an anti-helminthic drug, against LF-induced nephrotoxicity in mice. Forty male albino mice were randomly allocated into four groups. Group one acted as the control. Group two received LF at (10 mg/kg, P.O.). The third group was given both LF (10 mg/kg, P.O.) and PZQ (300 mg/kg, P.O.). Finally, the fourth group was given PZQ (300 mg/kg, P.O.). After eight weeks, the mice were euthanized following anesthesia, and their kidneys were extracted for biochemical and histopathological analysis. Leflunomide (LF) significantly increased serum creatinine (0.88 ± 0.01 mg/dL vs. 0.16 ± 0.01 mg/dL, p < 0.05) and BUN levels (69.15 ± 3.73 mg/dL vs. 32.52 ± 1.18 mg/dL, p < 0.05), while reducing albumin levels by 27.26%. Co-treatment with praziquantel (PZQ) markedly restored renal function, decreasing creatinine and BUN by 71.6% and 34.2%, respectively (p < 0.05), and increasing albumin by 1.2-fold. PZQ also significantly reduced oxidative stress markers (MDA 56.98%, p < 0.05) and pro-inflammatory cytokines (IL-6 - 73.69%, p < 0.05), while upregulating antioxidant (Nrf-2 + 6.7-fold) and anti-inflammatory (PPAR-γ + 3.1-fold) pathways. These statistically significant improvements confirm the nephroprotective efficacy of PZQ against LF-induced nephrotoxicity through modulation of TGF-β/Smad, Wnt/β-catenin, NF-κB, Nrf-2, and PPAR-γ signaling pathways.