Pitavastatin Strengthens the Barrier Integrity in Primary Cultures of Rat Brain Endothelial Cells
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Statins have a neuroprotective effect in neurological diseases, a pleiotropic effect possibly related to blood–brain barrier (BBB) function. We investigated the effect of pitavastatin on barrier functions of an in vitro BBB model with primary cultures of rat brain capillary endothelial cells (RBEC). Pitavastatin increased the transendothelial electrical resistance (TEER), an index of barrier tightness of interendothelial tight junctions (TJs), at a concentration of 10−8 M, and decreased the endothelial permeability for sodium fluorescein through the RBEC monolayer. The increase in TEER was significantly reduced in the presence of isoprenoid geranylgeranyl pyrophosphate, whereas farnesyl pyrophosphate had no effect on TEER. Our immunocytochemical and Western blot analyses revealed that treatment with pitavastatin enhanced the expression of claudin-5, a main functional protein of TJs. Our data indicate that pitavastatin strengthens the barrier integrity in primary cultures of RBEC. The BBB-stabilizing effect of pitavastatin may be mediated partly through inhibition of the mevalonate pathway and subsequent up-regulation of claudin-5 expression.
KeywordsPitavastatin Statins Blood–brain barrier Tight junctions Claudin-5 Transendothelial electrical resistance Geranyl geranylation Brain endothelial cells (rat)
Pitavastatin was obtained as a generous gift from Kowa Co., Ltd., Japan. We wish to thank Yasuko Yamashita, Takanori Shimono, and Tsuyoshi Izumo for their critical reviews of the manuscript and outstanding professional guidance. This work was supported by a Grant-in-Aid for Scientific Research (C) (21591848) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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