Protective Effects of Bee Venom ( Apis mellifera ) Against Cadmium‐Induced Hepatorenal Toxicity, Oxidative Stress, and Anxiety‐Like Behavior in Rats

ABSTRACT

Cadmium (Cd) is a persistent environmental heavy metal and a major public health concern because it persists in the body for long periods and gradually accumulates in vital organs, particularly the liver, kidneys, and brain. Chronic Cd exposure promotes the excessive production of reactive oxygen species (ROS), which ultimately leads to oxidative stress, inflammatory responses, organ dysfunction, and neurobehavioral alterations. Apis mellifera bee venom (BV) consists of a diverse mixture of biologically active peptides, including key components such as melittin and apamin with documented antioxidant, anti‐inflammatory, and neuroprotective properties. However, to date, no studies have directly investigated its potential to mitigate Cd‐induced multi‐organ toxicity. Therefore, the present study aimed to evaluate the protective effects of BV against Cd‐induced hepatorenal injury, oxidative imbalance, and anxiety‐like behavior in a rat model, and to investigate its potential as a natural therapeutic strategy against heavy metal‐induced systemic toxicity. Male Wistar rats were assigned to control, BV (1 mg/kg/day, subcutaneous route), Cd (40 mg/L in drinking water), and Cd + BV for 14 days. Anxiety‐like behavior was investigated using two behavioral tests, namely the elevated plus maze (EPM) and the open field test (OFT), while hepatic and renal function markers and oxidative stress parameters were quantified in plasma and tissue samples. BV composition was verified by RP‐HPLC ESI‐MS analysis, confirming melittin as the predominant peptide component. Cd exposure induced anxiety‐like behavior, elevated plasma ALT, AST, and urea levels, increased lipid peroxidation, and reduced antioxidant enzyme activities in brain, liver, and kidney. Co‐administration of BV markedly attenuated these behavioral and biochemical alterations, reducing MDA levels and restoring SOD and CAT activities. Collectively, these findings highlight the potential of BV to protect against Cd‐induced hepatorenal and neurobehavioral toxicity, likely through modulation of oxidative stress pathways, thereby underscoring its promise as a natural therapeutic candidate for mitigating oxidative damage induced by heavy metals.