Abstract
Hypoxia (Hx) is a component of many disease states including stroke. Ischemic stroke occurs when there is a restriction of cerebral blood flow and oxygen to part of the brain. During the ischemic, and subsequent reperfusion phase of stroke, blood-brain barrier (BBB) integrity is lost with tight junction (TJ) protein disruption. However, the mechanisms of Hx and reoxygenation (HR)-induced loss of BBB integrity are not fully understood. We examined the role of protein kinase C (PKC) isozymes in modifying TJ protein expression in a rat model of global Hx. The Hx (6% O2) induced increased hippocampal and cortical vascular permeability to 4 and 10 kDa dextran fluorescein isothiocyanate (FITC) and endogenous rat-IgG. Cortical microvessels revealed morphologic changes in nPKC- distribution, increased nPKCθ- and aPKC- protein expression, and activation by phosphorylation of nPKC-θ (Thr538) and aPKC- (Thr410) residues after Hx treatment. Claudin-5, occludin, and ZO-1 showed disrupted organization at endothelial cell margins, whereas Western blot analysis showed increased TJ protein expression after Hx. The PKC inhibition with chelerythrine chloride (5 mg/kg intraperitoneally) attenuated Hx-induced hippocampal vascular permeability and claudin-5, PKC ( and ) expression, and phosphorylation. This study supports the hypothesis that nPKC-θ and aPKC- signaling mediates TJ protein disruption resulting in increased BBB permeability.
Original language | English (US) |
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Pages (from-to) | 1847-1859 |
Number of pages | 13 |
Journal | Journal of Cerebral Blood Flow and Metabolism |
Volume | 30 |
Issue number | 11 |
DOIs | |
State | Published - Nov 2010 |
Keywords
- blood-brain barrier
- ischemia
- protein kinase C
- tight junction
- vascular permeability
ASJC Scopus subject areas
- Neurology
- Clinical Neurology
- Cardiology and Cardiovascular Medicine