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. 2008 Sep;39(9):2538-43.
doi: 10.1161/STROKEAHA.108.514927. Epub 2008 Jul 17.

"VSports app下载" Protecting against cerebrovascular injury: contributions of 12/15-lipoxygenase to edema formation after transient focal ischemia

Guang Jin  1 , Ken Arai, Yoshihiro Murata, Sophia Wang, Monique F Stins, Eng H Lo, Klaus van Leyen
Affiliations

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

Guang Jin (VSports最新版本) et al. Stroke. 2008 Sep.

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 ischemia-reperfusion. The current study was designed to investigate 12/15-LOX involvement in vascular injury in the ischemic brain. VSports手机版.

Methods: In cell culture, a human brain microvascular endothelial cell line was subjected to either hypoxia or H(2)O(2)-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 V体育安卓版. Edema was measured as water content of brain hemispheres according to the wet-dry weight method. .

Results: Brain endothelial cells were protected against hypoxia and H(2)O(2) 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 V体育ios版. 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. .

Conclusions: 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 VSports最新版本. .

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Figures

Figure 1
Figure 1
Cell injury after oxidative stress in transformed human brain endothelial (THBE) cells reduced by lipoxygenase (LOX) inhibition. Oxidative stress in THBE cells. A, A significant increase of cell injury was detected after 24 hours of treatment with H2O2 (100, 200, and 400 µmol/L), compared with control group (n=4). B, Treatment in the presence of the 12/15-LOX inhibitors baicalein or AA861 significantly protected THBE cells against 24 hours of 200 µmol/L H2O2 exposure (n=3, *P<0.05, **P<0.01). C, Cell injury after 24 hours of hypoxia was significantly reduced by treatment with 10 µmol/L baicalein (n=3, *P<0.05).
Figure 2
Figure 2
Lipoxygenase (LOX) increased in neurons and endothelial cells following transient focal ischemia. Double immunostaining for LOX (red, A, D, G) with the neuronal marker, NeuN (green, B), the endothelial cell marker CD31 (green, E), and the astrocyte marker glial fibrillary acidic protein (GFAP; green, H) in the peri-ischemic area of the cerebral cortex after 24 hours of transient MCAO. LOX expression was colocalized with the neuronal and endothelial cell markers, NeuN and CD31 (C, F), but not with the astrocytic marker GFAP (I). Scale bar: 30 µm.
Figure 3
Figure 3
Protection of endothelial tight junction protein claudin-5 by lipoxygenase inhibition. Double immunostaining for CD31 (A, D, G) with claudin-5 (B, E, H) in the sham control (A–C) and in the peri-ischemic cortex of either control-treated (D–F) or baicalein-treated (G–I) animals after transient MCAO. The claudin-5 staining colocalized with the endothelial marker CD31 in these 3 groups (C, F, I), but a decrease in the intensity of claudin-5 staining was shown at 24 hours after transient MCAO (E). The loss of claudin-5 staining was significantly reduced in the baicalein treatment group (H) without significant difference in CD31 staining. Scale bar: 50 µm.
Figure 4
Figure 4
Reduced extravasation of immunoglobulin G (IgG) through either lipoxygenase (LOX) inhibition or LOX gene knockout after transient focal ischemia. A, IgG staining was significantly reduced at 24 hours after transient MCAO in the group with baicalein treatment compared with control (compare baicalein with DMSO) as well as in ALOX15 knockout mice compared with wild-type mice (compare knockout with wild-type). B, A comparison of the integrated staining densities confirms the reduction in IgG staining, suggesting that baicalein treatment or ALOX15 gene knockout protects the BBB (*P<0.05, n=6).
Figure 5
Figure 5
Reduced edema formation through either lipoxygenase (LOX) inhibition or LOX gene knockout after transient focal ischemia. A, The water content in the brain was greatly reduced in the group with baicalein treatment at 24 hours after transient MCAO (**P<0.01, n=9). B, ALOX15 knockout mice had significantly reduced water content in the brain compared with wild-type mice (*P<0.05, n=8).
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