Leflunomide induced cardiac injury in adult male mice and bioinformatic approach identifying Nrf2/NF-κB signaling interplay.

Leflunomide (LFND) is an immunosuppressive and immunomodulatory disease-modifying antirheumatic drug (DMARD) that was approved for treating rheumatoid arthritis. LFND-induced cardiotoxicity was not fully investigated since its approval. We investigated the cardiac injury in male mice and identified the role of nuclear factor erythroid2-related factor 2/nuclear factor-κ B (Nrf2/NF-κB) signaling. Male albino mice were assigned into 5 groups as control, vehicle and LFND (2.5, 5 and 10 mg/kg). We investigated cardiac enzymes, histopathology and the mRNA expression of Nrf2, NF-κB, BAX and tumor necrosis factor-α (TNF-α). The bioinformatic study identified the interaction between LFND and Nrf2/NF-κB signaling; this was confirmed by amelioration in mRNA expression (0.5 to 0.34-fold decrease in Nrf2 and 2.6 to 4.61- fold increases in NF-κB genes and increased (1.76 and 2.625-fold) serum creatine kinase (CK) and 1.38 and 2.33-fold increases in creatine kinase-MB (CK-MB). Histopathological results confirmed the dose-dependent effects of LFND on cardiac muscle structure in the form of cytoplasmic, nuclear and vascular changes in addition to increased collagen deposits and apoptosis which were increased compared to controls especially with LFND 10 mg/kg. The current study elicits the dose-dependent cardiac injury induced by LFND administration with and highlighted, for the first time, dysregulation in Nrf2/NF-κB signaling.