Inhibition of Src activity decreases tyrosine phosphorylation of occludin in brain capillaries and attenuates increase in permeability of the blood-brain barrier after transient focal cerebral ischemia

Disruption of the blood-brain barrier (BBB) caused by cerebral ischemia can initiate the development and progression of brain injuries, which may lead to irreversible dysfunction of the central nervous system. It is likely that tyrosine phosphorylation of a membrane-associated tight junctional protein, occludin, is important for the interaction of occludin with intracellular proteins, ZO-1 to ZO-3, and it regulates vascular permeability. Little is known about the pathophysiological alterations of tight junctional proteins after transient focal cerebral ischemia. In this study, we examined the tyrosine phosphorylation of occludin in isolated brain capillaries after transient focal cerebral ischemia. We further examined the effects of the Src-family tyrosine kinase inhibitor, PP2, on the tyrosine phosphorylation of occludin and on vascular permeability and infarct volume. Transient focal ischemia increased the tyrosine phosphorylation of occludin in the isolated brain capillaries. The administration of PP2 attenuated this phosphorylation, which was coincident with an inhibition of BBB leakage and a decrease in infarct volume. These results suggest that the increase in the tyrosine phosphorylation of occludin in the brain capillaries may be linked to the disruption of tight junctions, whose disruption can cause dysfunction of the BBB and the consequent increase in infarct volume. Journal of Cerebral Blood Flow & Metabolism (2009) 29, 1099-1108; doi:10.1038/jcbfm.2009.30; published online 25 March 2009