Pramipexole mitigates rotenone-evoked hepatic injury by regulating inflammatory, antioxidant, apoptosis and NLRP3-mediated pyroptosis.

The environmental chemical rotenone, which is employed as a natural insecticide, is hazardous to many organs. Thus, this study aimed to elucidate the protective efficacy of an oral administration of pramipexole (PPX) at a dose of 0.5 mg/kg/d against rotenone-induced hepatocellular damage for 60 days. Rotenone administration caused significant hepatic dysfunction, as evidenced by elevated serum AST, ALT, GGT, and bilirubin levels, along with reduced total protein and albumin, indicating impaired liver function. PPX co-administration markedly attenuated these changes, restoring liver enzyme activities and protein levels toward normal values but without a significant effect on albumin level. Additionally, rotenone-induced dyslipidemia was evident through increased total cholesterol, triglycerides, LDL, and VLDL, and decreased HDL levels. PPX significantly improved these lipid disturbances, demonstrating its hypolipidemic potential. Oxidative stress markers revealed that rotenone elevated MDA and GSSG while decreasing SOD and GSH levels. PPX pretreatment notably restored antioxidant balance by reducing lipid peroxidation and enhancing GSH-dependent defenses. At the molecular level, rotenone upregulated pyroptotic (NLRP3, ASC, Caspase-1, GSDMD, IL-18) and inflammatory (TNF-α, IL-1β, MCP-1, MPO) markers while downregulating hepatic miRNA-143-3p expression. PPX co-treatment significantly reversed these alterations, demonstrating anti-inflammatory and anti-pyroptotic efficacy but without any significant effect on miRNA-143-3p. Histopathological and immunohistochemical analyses further confirmed PPX's hepatoprotective role, showing near-normal hepatic structure, reduced necrosis, and suppressed expression of apoptotic (caspase-3, BAX) and macrophage activation (CD68) markers. Overall, PPX pretreatment effectively ameliorated rotenone-induced hepatotoxicity through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, suggesting its potential therapeutic value in preventing toxin-induced liver injury.