Chlorfenapyr‐Induced Hippocampal Neurotoxicity Is Driven by Oxidative Stress‐Inflammation Crosstalk, Mitochondrial Dysfunction, and Neurotransmitter Dysregulation: Evidence From Curcumin‐Loaded Casein Nanoparticle Intervention

ABSTRACT Chlorfenapyr (CFP) is a pyrrole‐class insecticide. Acute exposure to CFP results in severe delayed neurotoxicity with potentially fatal outcomes. The mechanisms by which CFP exerts its neurotoxic effects are not fully understood, and no definitive treatment for acute CFP poisoning exists to date. Thus, the present study investigated the neurotoxic effects of CFP in male Wistar rats. Also, we evaluated the neuroprotective potential of curcumin (CUR) encapsulated in casein nanoparticles (CUR‐CasNPs) compared to free CUR. Sixty rats were randomly divided into six groups receiving control, CUR, CUR‐CasNPs, CFP, CFP + CUR, or CFP + CUR‐CasNPs orally for 30 consecutive days. CFP exposure significantly reduced hippocampal neurotransmitter levels, including dopamine, norepinephrine, and serotonin, decreased ATP content and pyruvate dehydrogenase activity, elevated oxidative and nitrosative stress markers such as malondialdehyde and nitric oxide, suppressed antioxidant defenses including glutathione, superoxide dismutase, catalase, and glutathione peroxidase, upregulated pro‐inflammatory cytokines (IL‐1β, TNF‐α), activated NF‐κB/COX‐2 signaling, and increased pro‐apoptotic gene expression (Bax, Caspase‐3) while downregulating anti‐apoptotic Bcl‐2 and Nrf2/HO‐1 signaling. Co‐administration of CUR‐CasNPs significantly mitigated these alterations, restoring neurotransmitter balance, enhancing antioxidant capacity, reducing inflammation and apoptosis, and preserving hippocampal microstructure more effectively than free CUR. Histological and ultrastructural analyses confirmed maintenance of neuronal architecture, reduced gliosis, and improved vascular integrity in CUR‐CasNPs‐treated rats. These findings demonstrate that nano‐formulation enhances CUR's stability, bioavailability, and overall neuroprotective efficacy, highlighting its potential as a therapeutic strategy to counteract CFP‐induced hippocampal neurotoxicity by simultaneously modulating oxidative stress, inflammatory pathways, apoptotic signaling, and energy metabolism