Circulating (poly)phenol metabolites blood-grain barrier transport and brain availability

Objectives/Background: (Poly)phenols have been extensively studied considering their beneficial brain-health effects, particularly regarding neurodegenerative disorders. Circulating metabolites resultant from colonic metabolism of dietary (poly)phenols are highly abundant in the bloodstream, though still marginally underexplored, particularly regarding their brain accessibility. Our goal is to disclose circulating (poly)phenol metabolites’ capability of reaching the brain, in silico, in vitro, and in vivo. Materials/Methods: For three selected (poly)phenol metabolites, in silico relevant molecular descriptors were obtained using Qikprop software. Metabolites’ blood-brain barrier (BBB) transport and further metabolism were assessed in human brain microvascular endothelial cells (HBMEC) in transwells. Their fate towards brain, liver, kidney, urine, and blood, was also assessed in Wistar rats upon injection. Both UPLC-MS/MS and untargeted analysis were employed. Results/Findings: The results from computational analysis indicate that all the studied metabolites can passively cross the BBB. Transport kinetics along time using HBMEC highlighted different BBB permeability rates of the (poly)phenol metabolites, with novel end-route metabolites appearing at the brain site. From in vivo experiments, we found that all the injected metabolites can almost immediately cross the BBB and reach the brain, though at distinct extents, presenting different tissue distribution rates. Conclusion: Overall, we proved the ability of three circulating (poly)phenol metabolites to reach the brain, in circulating concentrations, with the ultimate potential to tackle neurodegeneration.