Protecting against cerebrovascular injury: Contributions of 12/15-lipoxygenase to edema formation after transient focal ischemia

Guang Jin, Ken Arai, Yoshihiro Murata, Sophia Wang, Monique F. Stins, Eng H. Lo, Klaus Van Leyen

Research output: Contribution to journalArticle

Abstract

BACKGROUND AND PURPOSE: The concept of the neurovascular unit suggests that effects on brain vasculature must be considered if neuroprotection is to be achieved in stroke. We previously reported that 12/15-lipoxygenase (12/15-LOX) is upregulated in the peri-infarct area after middle cerebral artery occlusion in mice, and 12/15-LOX contributes to brain damage after ischemiareperfusion. The current study was designed to investigate 12/15-LOX involvement in vascular injury in the ischemic brain. METHODS: In cell culture, a human brain microvascular endothelial cell line was subjected to either hypoxia or H2O2-induced oxidative stress with or without lipoxygenase inhibitors. For in vivo studies, mice were subjected to 90 minutes middle cerebral artery occlusion, and the effects of either 12/15-LOX gene knockout or treatment with lipoxygenase inhibitors were compared. Expression of 12/15-LOX and claudin-5 as well as extravasation of immunoglobulin G were detected by immunohistochemistry. Edema was measured as water content of brain hemispheres according to the wetdry weight method. RESULTS: Brain endothelial cells were protected against hypoxia and H2O2 by the lipoxygenase inhibitor baicalein. After focal ischemia, 12/15-LOX was increased in neurons and endothelial cells. The vascular tight junction protein claudin-5 underwent extensive degradation in the peri-infarct area, which was partially prevented by the lipoxygenase inhibitor baicalein. Leakage of immunoglobulin G into the brain parenchyma was significantly reduced in 12/15-LOX knockout mice as well as wild-type mice treated with baicalein. Likewise, brain edema was significantly ameliorated. CONCLUSION: 12/15-LOX may contribute to ischemic brain damage not just by causing neuronal cell death, but also by detrimental effects on the brain microvasculature. 12/15-LOX inhibitors may thus be effective as both neuroprotectants and vasculoprotectants.

Original languageEnglish (US)
Pages (from-to)2538-2543
Number of pages6
JournalStroke
Volume39
Issue number9
DOIs
StatePublished - Sep 1 2008

Keywords

  • Baicalein
  • Blood-brain barrier
  • Edema
  • Endothelial cell
  • Lipoxygenase

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

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