Role of Rho kinase in lysophosphatidic acid-induced altering of blood-brain barrier permeability

Abstract

Lysophosphatidic acid (LPA) the simplest of the water-soluble phospholipids, is produced by activated platelets, macrophage and endothelial cells. It also evokes various biological responses. When LPA concentrations reach high levels, brain injury, including stroke and intracerebral hemorrhage (ICH), occurs. Previous studies have shown that LPA is crucial in increasing blood-brain barrier (BBB) permeability, and the Rho/Rho kinase (ROCK) signaling pathway is involved in the regulation of endothelial permeability. However, the exact mechanism by which the Rho/ROCK pathway mediates BBB disruption induced by LPA remains to be determined. In the present study, we observed that LPA induced the increase of BBB permeability in the right striatum after 10 µl LPA (100 µM) was injected into the ipsilateral caudate nucleus of rats. The ROCK was involved in the expression of proteolytic enzymes, matrix metalloproteinase (MMP)-9 and urokinase-type plasminogen activator (uPA), leading to LPA-induced BBB disruption. ROCK inhibitor (Y27632) markedly inhibited the expression of proteolytic enzymes induced by LPA as well as the BBB disruption after it was co-injected with LPA. Thus, results of the present study suggest that LPA increases BBB permeability, which may be due to the Rho/ROCK signaling pathway and the subsequent production of proteolytic enzymes MMP-9 and uPA.