Apilarnil protects against the copper nanoparticle hepato-renal toxicity in rats associated with oxidative stress, inflammation, apoptosis, autophagy

This study aimed to investigate the protective effects of apilarnil against hepatorenal damage induced by copper nanoparticles in rats. A total of 35 rats were randomly divided into five groups (n = 7): Control (physiological saline), APL (400 mg/kg apilarnil), Cu (100 mg/kg copper nanoparticles), Cu + APL 200 (100 mg/kg copper + 200 mg/kg apilarnil) and Cu + APL 400 (100 mg/kg copper + 400 mg/kg apilarnil). All treatments were administered orally by gavage for 28 days. In the copper nanoparticle-treated group, significant decreases in antioxidant enzyme activities, including superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT), as well as reduced glutathione (GSH) levels, were observed, accompanied by a marked increase in malondialdehyde (MDA) levels compared to the control group. Apilarnil administration significantly attenuated oxidative stress by restoring antioxidant parameters and reducing MDA levels toward control values. Copper nanoparticle exposure activated autophagy-related signaling pathways through phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT3), and mammalian target of rapamycin (mTOR). Additionally, it induced endoplasmic reticulum (ER) stress via increased expression of activating transcription factor 6 (ATF6), glucose-regulated protein 78 (GRP78), protein kinase RNA-like ER kinase (PERK), and C/EBP homologous protein (CHOP). Copper exposure also elevated inflammatory markers, including Toll-like receptor 4 (TLR4), high mobility group box-1 (HMGB-1), nuclear factor-kappa B (NF-κB), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α). Apilarnil treatment effectively suppressed autophagy activation, ER stress, and inflammatory responses, demonstrating pronounced antioxidant, anti-inflammatory, and antiautophagic effects. These findings suggest that apilarnil may serve as a potential alternative therapeutic agent against copper nanoparticle-induced liver and kidney toxicity.