Neonatal propofol exposure induces region-specific neurotoxic proteomic signatures in mouse cortex and hippocampus.

Neonatal propofol exposure has been implicated in long-term neurodevelopmental impairments; however, region-specific molecular mechanisms remain unclear. This study examined region-specific proteomic alterations in exosome-enriched small extracellular vesicles (exosome-enriched sEVs) from the cortex and hippocampus induced by neonatal propofol exposure. Using a clinically relevant repeated-dose regimen, C57BL/6 mice received propofol (50  mg/kg, P5-P7). At P21, exosome-enriched sEVs were isolated and analyzed by data-independent acquisition mass spectrometry. Candidate differentially expressed proteins (candidate DEPs) were defined by fold change (FC) ≥ 1.5 or ≤ 0.667 and nominal p < 0.05, followed by Gene Ontology (GO), KEGG pathways, Cluster of Orthologous Groups (COG), and domain enrichment analyses. After Benjamini-Hochberg correction, no protein reached q < 0.05, indicating that the exploratory findings were not significant. We identified 63 candidate DEPs in the hippocampus and 55 in the cortex. Hippocampal downregulated proteins enriched in synaptic vesicle cycling, oxidative phosphorylation, and apoptosis, suggesting synaptic-mitochondrial disruption; upregulated proteins associated with ER stress and chaperone-mediated autophagy, suggesting proteostatic adaptation. Cortical candidate DEPs reflected suppressed mitochondrial function alongside enhanced translation and cytoskeletal remodeling. These region- and direction-specific changes were consistently observed across all bioinformatic platforms. The hippocampus showed pronounced synaptic and mitochondrial alterations, while the cortex exhibited cytoskeletal changes and metabolic shifts. In conclusion, Propofol induces distinct neurotoxic proteomic signatures in the neonatal hippocampus and cortex, suggesting compartment-specific vulnerability and compensatory remodeling. Thus, exosome-enriched sEV proteomics offers a sensitive approach to detecting early anesthetic-induced neurodevelopmental disturbances.