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Increasing evidence suggest that dietary (poly)phenols and methylxanthines have neuroprotective effects, however little is known on whether they can cross the blood brain barrier (BBB) and exert direct effects in the brain. This work aimed to investigate the presence of (poly)phenol and methylxanthine metabolites in cerebrospinal fluid (CSF), and to predict the mechanism of transport of these compounds across the BBB using in silico modelling techniques. (Poly)phenol and methylxanthine metabolites were analyzed in plasma and CSF samples from 90 individuals at risk of dementia aged 60 to 80 using liquid chromatography coupled to mass spectrometry and authentic standards. In silico prediction algorithms were used to decipher which metabolites could cross the BBB by passive diffusion from those who might require other mechanisms of transport. A total of 123 and 127 metabolites were detected in CSF and plasma, respectively. From those, the levels of 20 metabolites were quantified in CSF, while 123 were quantified in plasma. The most abundant metabolites present in all volunteers were hippuric acid in plasma and 3-hydroxybenzoic acid in CSF, with concentrations of 387 ± 243 μM and 367 ± 292 nM, respectively. In silico analysis suggests that 5 of the 20 metabolites detected in CSF can cross the BBB by passive diffusion, while at least 9 metabolites showed some level of saturation in CSF upon increasing plasma concentrations, suggesting that these metabolites require the aid of cell transporters to cross the BBB. The remaining metabolites might require the help of both mechanisms of transport, but further studies are needed to confirm this. Our results showed that a wide range of metabolites coming from the habitual diet are bioavailable in plasma and can cross the BBB via passive diffusion or transport carriers, based on their structure. These findings confirm that (poly)phenols and methylxanthines can reach brain tissues to exert neuroprotective effects.
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