title: Interaction between flavonoids and the blood-brain barrier: in vitro studies.
abstract: There is considerable current interest in the neuroprotective effects of flavonoids. This study focuses on the potential for dietary flavonoids, and their known physiologically relevant metabolites, to enter the brain endothelium and cross the blood-brain barrier (BBB) using well-established in vitro models (brain endothelial cell lines and ECV304 monolayers co-cultured with C6 glioma cells). We report that the citrus flavonoids, hesperetin, naringenin and their relevant in vivo metabolites, as well as the dietary anthocyanins and in vivo forms, cyanidin-3-rutinoside and pelargonidin-3-glucoside, are taken up by two brain endothelial cell lines from mouse (b.END5) and rat (RBE4). In both cell types, uptake of hesperetin and naringenin was greatest, increasing significantly with time and as a function of concentration. In support of these observations we report for the first time high apparent permeability (Papp) of the citrus flavonoids, hesperetin and naringenin, across the in vitro BBB model (apical to basolateral) relative to their more polar glucuronidated conjugates, as well as those of epicatechin and its in vivo metabolites, the dietary anthocyanins and to specific phenolic acids derived from colonic biotransformation of flavonoids. The results demonstrate that flavonoids and some metabolites are able to traverse the BBB, and that the potential for permeation is consistent with compound lipophilicity.
authors.affiliation: Antioxidant Research Group, Wolfson Center for Age-Related Diseases, Centre for Neuroscience Research, Guy's, King's and St Thomas's School of Biomedical Sciences, King's College, London, UK.
authors.forename: Kuresh A
authors.initials: KA
authors.lastname: Youdim
authors.forename: Michael S
authors.initials: MS
authors.lastname: Dobbie
authors.forename: Gunter
authors.initials: G
authors.lastname: Kuhnle
authors.forename: Anna R
authors.initials: AR
authors.lastname: Proteggente
authors.forename: N Joan
authors.initials: NJ
authors.lastname: Abbott
authors.forename: Catherine
authors.initials: C
authors.lastname: Rice-Evans
mesh_terms: D000818:Animals; D000872:Anthocyanins / Q000378:metabolism / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000098:blood supply; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D044950:Flavanones; D005419:Flavonoids / Q000378:metabolism* / Q000493:pharmacokinetics*; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism*; D020719:Glucuronides / Q000378:metabolism / Q000493:pharmacokinetics; D006569:Hesperidin / Q000378:metabolism / Q000493:pharmacokinetics; D013058:Mass Spectrometry; D051379:Mice; D008833:Microcirculation / Q000166:cytology; D051381:Rats
chemical_list: D000872:Anthocyanins; D044950:Flavanones; D005419:Flavonoids; D020719:Glucuronides; C078485:pelargonidin-3-glucoside; D006569:Hesperidin; C005273:naringenin; C428983:cyanidin 3-rutinoside; C013015:hesperetin