Attenuation of imidacloprid deleterious effect on hepatic and neural tissues via acetylsalicylic acid: targeting HMGB1/caspase-3 axis and inflammatory pathway

Abstract Imidacloprid (IMID), a neonicotinoid insecticide, is widely utilized but has been implicated in systemic toxicities affecting hepatic, renal, and cerebral tissues. Recent observations indicate concurrent field application of IMID with acetylsalicylic acid (ASA), producing synergistic in plant protection. This study investigates the modulatory impact of ASA on IMID-induced hepatoneurotoxicity in male albino rats. Rats ( n  = 20) were allocated into four experimental groups: control, ASA-treated (40 mg/kg b.w.), IMID-treated (20 mg/kg b.w.), and IMID + ASA combination. Serum biomarkers of hepatic injury such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, and total protein were estimated alongside brain acetylcholinesterase (AchE) activity. Oxidative stress parameters were assessed by measuring malondialdehyde (MDA) concentrations and antioxidant enzyme activities, specifically superoxide dismutase (SOD) and catalase (CAT), in liver and brain homogenates. Gene expression of pro-inflammatory cytokine, including high mobility group box 1 (HMGB1), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), and immunohistochemical expression of nuclear factor kappa B (NF-κB P65) were analyzed. IMID exposure resulted in significant hepatocellular and neuronal damage characterized by elevated serum ALT and AST, hypoalbuminemia, hypoproteinemia, increased MDA, suppression of SOD and CAT activities, and upregulated mRNA expression of TNF-α, IL-6, and HMGB1. Co-administration of ASA markedly mitigated these biochemical and histopathological alterations, normalizing antioxidant defenses and downregulating inflammatory mediators and NF-κB activation. The obtained results suggest that ASA is not toxic in this context and may actually protect against the liver and brain damage caused by IMID by dampening the oxidative stress and inflammatory responses driven by HMGB1 and NF-κB.