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 (P app ) 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. Keywords: blood-brain barrier, flavonoids, glucuronidation, hesperetin, naringenin, neuroprotection. There is growing interest in dietary therapeutic strategies to combat oxidative stress-induced damage to the CNS associated with a number of pathophysiological processes, including Alzheimer's disease, cerebrovascular disease such as strokes or lesions, Parkinson's disease, Creutzfeldt-Jakob disease and certain traumas (Coyle and Puttfarcken 1993;Cantuti-Castelvetri et al. 2000). In addition, changes in the optimal performance of the CNS may occur simply as a function of ageing, possibly exacerbating the motor and cognitive behavioural changes seen in these conditions (Shukitt-Hale 1999). Recent studies have highlighted an important role for the neuroprotective actions of dietary components, including flavonoids found in fruit, vegetables and plant-derived beverages (for a review see Abbreviations used: BBB, blood-brain barrier; b.END5, brain endothelial cell line from mouse; bFGF, basic fibroblast growth factor; BSA, bovine serum albumin; C3R, cyanidin-3-rutinoside; DMEM, Dulbecco's modified Eagle medium; FBS, fetal bovine serum; FCS, fetal calf serum; HPLC, high-performance liquid chromatography; MTT, 2-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; OATP, organic anion transport polypeptide; P3G, pelargonidin-3-glucoside; P app , apparent permeability; PBS, phosphate-buffered saline; P-gp, P-glycoprotein; RBE4, brain endothelial cell line from rat; RT, retention time; TEER, transendothelial electrical resistance.

Modulation of Pro-survival Akt/Protein Kinase B and ERK1/2 Signaling Cascades by Quercetin and Its in Vivo Metabolites Underlie Their Action on Neuronal Viability

“…Potential toxicity of flavonoids such as quercetin toward neuronal cells in vivo may be limited by the action of the blood-brain barrier preventing the entry of such compounds to the brain. However, recent evidence has demonstrated that flavonoids and some of their metabolites are able to traverse the blood-brain barrier and that the potential for permeation is consistent with compound lipophilicity (55). Indeed quercetin, and especially its O-methylated metabolites, have relatively high lipophilicity, indicating the potential brain access of these compounds.…”

Improving the oral bioavailability of beneficial polyphenols through designed synergies

“…Work by Youdim et al [89] using an in vivo BBB permeability model showed that the common flavonoid quercetin has very little access through the BBB. Coadministration of quercetin with the Pgp inhibitor PSC833 had no effect on its entry, but co-administration with the BCRP inhibitor GF120918 caused a 20-fold increase in quercetin entry into the brain.…”

The interactions of flavonoids within neuronal signalling pathways

“…In order for flavonoids to enter into the brain, they must first cross the blood brain barrier (BBB). The function of the BBB includes protection of the brain from xenobiotics and the general maintenance of the brain's microenvironment [2,193]. Studies by Youdim et al indicated that certain flavonoids were able to penetrate the BBB in relevant in vitro and in situ models [193,195,196].…”