Metabolic reprogramming of hippocampal endothelial cells contributes to blood-brain barrier dysfunction in perioperative neurocognitive disorder.

BACKGROUND

The increasing demand for anesthesia and surgical interventions, driven by an aging population, has brought renewed attention to perioperative neurocognitive disorder (PND)-a condition characterized by cognitive decline occurring in the perioperative period. Up to 30 % of elderly surgical patients are reported to develop PND, often accompanied by blood-brain barrier (BBB) dysfunction. However, how endothelial metabolic reprogramming contributes to BBB dysfunction during PND remains poorly understood.

METHODS

We established a mouse model of PND using isoflurane anesthesia combined with unilateral nephrectomy. Cognitive performance was assessed via Y-maze and fear conditioning tests. Hippocampal endothelial cells were isolated post-surgery and analyzed using liquid chromatography-mass spectrometry (LC-MS). Metabolites involved in amino acid, lipid, nucleotide, and carbohydrate metabolism were quantified and analyzed.

RESULTS

Anesthesia and surgery led to significant cognitive decline. Transmission electron microscopy (TEM) revealed ultrastructural alterations in the hippocampus and BBB dysfunction, including perivascular edema and changes in the basement membrane and tight junctions. Metabolomic profiling revealed 12 significantly upregulated and 96 downregulated metabolites in hippocampal endothelial cells. KEGG pathway enrichment analysis identified prominent alterations in arginine and proline metabolism, glutathione metabolism, and aminoacyl-tRNA biosynthesis. Differential metabolites-such as succinate, tyrosine, guanethidine, chloramphenicol, indinavir, and olmesartan-were associated with multiple metabolic pathways. Consistent with these metabolite changes, the expression of key metabolic enzyme genes was markedly altered in hippocampal endothelial cells.

CONCLUSIONS

Anesthesia and surgery induce metabolic reprogramming in hippocampal endothelial cells, alterations pathways central to amino acid, lipid, nucleotide, and carbohydrate metabolism. These endothelial metabolic alterations may underlie BBB dysfunction and contribute to the pathogenesis of PND.