Ischemia-reperfusion impairs blood-brain barrier function and alters tight junction protein expression in the ovine fetus

Neuroscience. 2012 Dec 13;226:89-100. doi: 10.1016/j.neuroscience.2012.08.043. Epub 2012 Sep 15.


The blood-brain barrier is a restrictive interface between the brain parenchyma and the intravascular compartment. Tight junctions contribute to the integrity of the blood-brain barrier. Hypoxic-ischemic damage to the blood-brain barrier could be an important component of fetal brain injury. We hypothesized that increases in blood-brain barrier permeability after ischemia depend upon the duration of reperfusion and that decreases in tight junction proteins are associated with the ischemia-related impairment in blood-brain barrier function in the fetus. Blood-brain barrier function was quantified with the blood-to-brain transfer constant (K(i)) and tight junction proteins by Western immunoblot in fetal sheep at 127 days of gestation without ischemia, and 4, 24, or 48 h after ischemia. The largest increase in K(i) (P<0.05) was 4 h after ischemia. Occludin and claudin-5 expressions decreased at 4 h, but returned toward control levels 24 and 48 h after ischemia. Zonula occludens-1 and -2 decreased after ischemia. Inverse correlations between K(i) and tight junction proteins suggest that the decreases in tight junction proteins contribute to impaired blood-brain barrier function after ischemia. We conclude that impaired blood-brain barrier function is an important component of hypoxic-ischemic brain injury in the fetus, and that increases in quantitatively measured barrier permeability (K(i)) change as a function of the duration of reperfusion after ischemia. The largest increase in permeability occurs 4 h after ischemia and blood-brain barrier function improves early after injury because the blood-brain barrier is less permeable 24 and 48 than 4 h after ischemia. Changes in the tight junction molecular composition are associated with increases in blood-brain barrier permeability after ischemia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Algorithms
  • Aminoisobutyric Acids
  • Animals
  • Blood Volume / physiology
  • Blood-Brain Barrier / physiopathology*
  • Blotting, Western
  • Brain / embryology
  • Brain Ischemia / physiopathology
  • Carotid Arteries / physiology
  • Claudin-1 / biosynthesis
  • Claudin-5 / biosynthesis
  • Densitometry
  • Electroencephalography
  • Erythrocytes / physiology
  • Female
  • Fetus / physiology*
  • Occludin / biosynthesis
  • Reperfusion Injury / physiopathology*
  • Sheep
  • Technetium
  • Tight Junction Proteins / biosynthesis*
  • Tight Junctions / metabolism*


  • Aminoisobutyric Acids
  • Claudin-1
  • Claudin-5
  • Occludin
  • Tight Junction Proteins
  • Technetium