Baicalin alleviates lead-induced cognitive dysfunction by modulating apoptosis and autophagy in mice.

Lead exposure is a well-documented environmental neurotoxin that poses a persistent threat to brain development. Excessive lead accumulation in this region impairs cognitive function and induces neuronal damage, yet effective therapeutic interventions remain limited. Baicalin, a flavonoid compound derived from Scutellaria baicalensis, exhibits antioxidant and neuroprotective activity, but its efficacy against lead-induced neural injury has not been fully elucidated. Here, we established a subchronic lead exposure model in mice and administered baicalin orally following lead treatment. Cognitive function was assessed through spatial, recognition, and avoidance learning paradigms. Lead concentrations in blood and hippocampus, as well as hippocampal structural integrity, oxidative stress markers, apoptosis signals, and neuronal autophagy, were quantitatively analyzed. In vitro studies using HT22 cells further investigated the effects of baicalin on oxidative stress, mitochondrial function, and autophagy-related signaling pathways. Baicalin treatment significantly improved cognitive performance, reduced blood and hippocampal lead concentrations, preserved hippocampal morphology, and reestablished redox homeostasis. Baicalin reduced lipid peroxidation, suppressed neuronal apoptosis, and restored autophagic flux. Mechanistically, baicalin activated AMPK, inhibited mTOR phosphorylation, and promoted ULK1-mediated autophagy. These effects were abolished by pharmacological inhibition of AMPK, confirming the pivotal regulatory role of baicalin. Collectively, these findings demonstrate that baicalin mitigates lead-induced cognitive and neuronal impairments by modulating oxidative stress, apoptosis, and autophagy via the AMPK-mTOR-ULK1 signaling axis. These results support further investigation of baicalin as a candidate neuroprotective agent for managing heavy metal-associated neurodevelopmental disorders.