Reoxygenation stress on blood–brain barrier paracellular permeability and edema in the rat

Abstract

The blood-brain barrier (BBB) serves as a critical regulator of brain homeostasis. Following hypoxia (i.e. 6% oxygen/1hr) and reoxygenation (H/R), the BBB tight junctional complex is disrupted, resulting in increased BBB permeability and the development of vasogenic brain edema. In this study, we examined the effect of H/R on the in vivo rat BBB over a 36 hr time course in conjunction with paracellular permeability, grey matter edema, and systemic inflammatory activity. A biphasic increase was observed in the brain uptake of 14 C-sucrose, a paracellular permeability marker; with the first increase at the 10 min reoxygenation time point, and the second increase at the 6−18hr time points. Increased brain water weight gain (edema) also showed a biphasic response with the first increase at the 10 min-1 hr reoxygenation time points; and the second increase at only the 24 hr time point). Analysis of serum derived cytokines (IL-1β, TNFα, IL-6, IL-10, & IFNγ) demonstrated that only IL-1β and IL-6 were at detectable levels, but these levels were similar to controls. White bloodcell counts showed significant decreases in lymphocytes (10 min-3 hr), increases in monocytes (10 min-3 hr & 12 hr), and increases in polymorphonuclear cells (1hr & 3 hr). We have shown that H/R elicits a biphasic increase in paracellular permeability and edema, which parallel to post-stroke sequelae, despite the lack of occlusion or complete depletion of oxygen.

Biphasic Modulation of Paracellular Claudin-5 Expression in Mouse Brain Endothelial Cells Is Mediated through the Phosphoinositide-3-Kinase/AKT Pathway

“…We extended the time course out to 1, 2, or 3 days of 3-chloropropanediol exposure, and claudin-5 expression was again observed to be lost from paracellular domains and was accompanied by a loss of total claudin-5 protein expression. This early and late response in paracellular tight junction protein expression is consistent with previous in vivo and in vitro studies that report a similar biphasic loss of BBB integrity with increased permeability (Witt et al, 2008;Jiao et al, 2011). Jiao and colleagues (2011) used a focal cerebral ischemia model and showed a biphasic increase of BBB permeability, with an initial change at 3 hours followed by a second change at 72 hours after injury.…”

Oxidative Stress Increases Blood–Brain Barrier Permeability and Induces Alterations in Occludin during Hypoxia–Reoxygenation

“…Cerebral HR occurs during stroke and microvascular infarcts, vascular dementia, cardiac arrest, postoperative cognitive dysfunction, acute respiratory distress syndrome, obstructive sleep apnea, and high-altitude cerebral edema. We have previously shown that HR causes an increase in paracellular permeability at the BBB (Witt et al, 2003;Witt et al, 2008). We have also shown changes in occludin protein localization and oligomeric assemblies that are associated with HR (McCaffrey et al, 2009).…”

Protein Kinase C Activation Modulates Reversible Increase in Cortical Blood–Brain Barrier Permeability and Tight Junction Protein Expression during Hypoxia and Posthypoxic Reoxygenation

“…Previous studies in our laboratory have shown increased [ 14 C]-sucrose permeability and edema formation with changes in occludin protein expression in cerebral microvessels after Hx and HR exposure (Witt et al, 2003(Witt et al, , 2008. Total PKC activity in isolated cerebral microvessels was also increased, whereas HR (10 minutes) attenuated the increased total PKC activity.…”

“…Studies show that specific brain regions are vulnerable to global cerebral ischemia/Hx, especially the hippocampal CA1 pyramidal neurons and cortical neurons, whereas other regions are more resistant (Pulsinelli et al, 1982;Himeda et al, 2005). During the ischemic, and subsequent reperfusion phase of stroke, the integrity of the blood-brain barrier (BBB) is lost (Mark and Davis, 2002;Witt et al, 2003Witt et al, , 2008. Elucidating the mechanisms of Hx and reoxygenation (HR)-induced changes in BBB integrity remains a considerable task.…”