Metabolic Profiling of a Mediterranean-Inspired (Poly)phenol-Rich Mixture in the Brain: Perfusion Effect and <i>In Vitro</i> Blood–Brain Barrier Transport Validation

A Mediterranean diet rich in (poly)phenols has been linked to neuroprotection, but its effects likely depend on the ability of phenolic metabolites to cross the blood-brain barrier (BBB). This study evaluated the kinetics plasma and brain distribution of phenolic metabolites in Sprague-Dawley rats following oral administration of a polyphenol-rich extract mixture from Mediterranean foods (pomegranate, lemon, orange, grape, and olive). UPLC-ESI-QTOF analyses revealed 39 phenolic-derived metabolites in plasma, of which 20 were in nonperfused (NPB) and 19 in perfused brains (PB), including hydroxytyrosol and tyrosol sulfates, ellagic acid, dihydrocaffeic acid, and derived metabolites. Kinetic data showed substantially higher plasma metabolite concentrations than the brain, with slightly higher levels in NPB. The BBB transport efficiency of phenolic metabolites was validated <i>in vitro</i> using human brain microvascular endothelial cells (HBMECs), showing improved transport when tested as mixtures. These findings confirm that circulating phenolic metabolites from Mediterranean foods can reach brain tissues, contributing to preventing neurodegenerative diseases.