A new blood-brain barrier(BBB) model : Specific uses under in vitro conditions of brain diseases

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Seven different types of blood-brain barrier(BBB)models, mono-culture, double and triple co-cultures, were constructed from primary rat brain endothelial cells, astrocytes and pericytes on culture inserts. The barrier integrity of the models were compared by measurement of transendothelial electrical resistance and permeability for the small molecular weight marker fluorescein. We could confirm that brain endothelial monolayers in mono-culture do not form tight barrier. Pericytes induced higher electrical resistance and lower permeability for fluorescein than type I astrocytes in co-culture conditions. In triple co-culture models the tightest barrier was observed when endothelial cells and pericytes were positioned on the two sides of the porous filter membrane of the inserts and astrocytes at the bottom of the culture dish(BBB kit). With the BBBkit, we investigated effects and permeability on the BBB of centrally acting drugs under in vitro stimulations of prion protein fragment PrP106-126, amyloid-B peptide(1-42), and hypoxia(BBB kit disease models).Edaravone, a clinically-widely used anti-brain edema drug, markedly defended the BBB disruption due to a transient cerebral ischemia. PPS, a candidate drug for prion disease, penetrated more rapidly on the BBB under PrP106-126. Cilostazol increased the activity of P-glycoprotein of the BBB kit under hypoxia and histamine, an in vitro model of the brain edema. Thus, our BBB kit was found to be a suitable in vitro-experimental tool to study drug-permeability on the BBB under pathological conditions.