INTERACTION BETWEEN DIETARY FLAVONOIDS AND THE BRAIN BARRIER
Kuresh Youdim, M. Zeeshan Qaiser, Catherine A. Rice-Evans & N. Joan Abbott
Antioxidant Research Group, Wolfson Centre for Age-Related Diseases,
and Blood-Brain Barrier Group, Centre for Neuroscience Research, Guy's
King's and St Thomas's School of Biomedical Sciences, King's College,
London SE1 1UL
Recent studies highlight an exciting role with respect to the
neuroprotective actions of dietary flavonoids. The mechanisms
associated with flavonoid neuroprotection is complicated by the lack of
information about their ability to enter the CNS. However, we have
shown recently, using an in vitro blood-brain barrier (BBB) model
(ECV304 co-cultured with C6 glioma cells) that flavonoids including
their physiologically relevant metabolites exhibit high apparent
permeability (Papp) across the brain endothelium. Using [3H]
naringenin and [14C] quercetin as model substrates we have also shown
in vivo, accumulation into 7 brain regions (cerebellum, cortex,
hippocampus, hypothalamus, striatum, superior colliculus, and
medulla). Total uptake (Kin ?L min-1 g-1) of naringenin was high in
all regions studied, suggesting significant passive permeability. In
contrast quercetin uptake was comparable to the P-glycoprotein (P-gp)
efflux transporter substrate, colchicine. The potential influence of
efflux transporters in mediating quercetin permeability in vivo, was
studied by pre-administering animals with P-gp inhibitors PSC833 and
GF120918 (10mg/kg). Only GF120918 significantly effected uptake. A
closer examination of the role played by efflux transporters on
flavonoid flux across the BBB was performed using MDCK-MDR1 and rat
brain endothelial cells (RBE4) (both expressing functional P-gp). Our
in vitro findings support observations in vivo, where flavonmoid
accumulation was greatest in cells exposed to GF120918. In conclusion,
these studies demonstrate that flavonoids are able to permeate the BBB
but that some are possible substrates for efflux transporters, which
limit their CNS bioavailability.
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