Nigar Abbak, Emirhan Nemutlu, Tuba Reçber, Asli San Dagli Gul, Fatma Bahar Sunay, Okan Arihan
Cadmium (Cd) is a toxic heavy metal that causes multi-organ damage, including neurotoxicity. Carvacrol (CAR), a natural phenolic compound obtained from aromatic plants, is known for its protective properties. This study investigated the effects of CAR against Cd-induced toxicity through comprehensive behavioral assessments including the Open Field Test (OFT), Elevated Plus Maze (EPM), Barnes Maze, and Rotarod test, while plasma biochemical parameters, liver and kidney histopathology, and untargeted metabolomic profiles (plasma and brain) were also evaluated. Male Wistar albino rats were randomly divided into six groups and orally administered Cd (50 mg/kg) and/or CAR (20 or 40 mg/kg body weight) for 12 days. CAR alone increased locomotor activity, altered neuroprotective related metabolic pathways and did not cause weight loss. Cd exposure significantly increased body weight loss and anxiety-like behaviors while elevating cortisol, urea, AST, ALT levels and inducing significant histopathological damage in liver and kidney tissues (p < 0.05). Integrated plasma-brain metabolomic analyses revealed that Cd exposure disrupts multiple interconnected biological systems, including the antioxidant defence system, mitochondrial energy pathways, and cell membrane integrity. Although Cd-CAR co-administration partially reversed worsening of the anxiolytic-like behavior, locomotor activity, and renal tissue integrity, it failed to fully prevent Cd-induced toxicity and further aggravated weight loss, biochemical alterations (creatinine, AST, ALT), and metabolic disturbances (p < 0.05). In conclusion, co-administration of CAR with Cd provided only limited and heterogeneous protection that was insufficient to counteract Cd-induced multisystem toxicity. This current study presents a wide assessment to the systemic use of CAR against Cd according to results of behavioral, histopathological, biochemical, and metabolomic parameters.