Neutrophil elastase inhibitor prevents ischemic brain damage via reduction of vasogenic edema.
Release of neutrophil elastase is one of the harmful inflammatory reactions in acute cerebral ischemia. Therefore, inhibition of elastase released from neutrophils could be a useful strategy for the treatment of acute stroke. To evaluate this hypothesis, the effect of sivelestat, a selective neutrophil elastase inhibitor was examined in a mouse model of focal ischemia. The results obtained indicate that sivelestat reduced brain edema and vascular permeability, and subsequently improved the neurological deficit in an acute focal ischemia. The architecture of microvessels was analyzed by identifying vascular endothelial cells, which were prelabeled by injecting fluorescein-labeled Griffonia simplicifolia lectin I-isolectin B4 into a tail vein. Most of the microvessels in the infarcted area were structurally destroyed in the control group. In sharp contrast, microvessels in the boundary zone were well maintained in the sivelestat-treated group. Moreover, the expression of angiopoietin-1 was elevated at the ischemic margin in the sivelestat-treated group. Furthermore, the neutrophil elastase inhibitor rescued human brain microvascular endothelial cells in culture from neutrophil elastase-induced damage. These results suggest that neutrophil elastase inhibition could protect blood-brain barrier function in acute cerebral ischemia by augmentation of angiopoietin-1 expression and survival of endothelial cells.
Ikegame
Yuka
Y
Department of Neurosurgery, Gifu University Graduate School of Medicine, Gifu, Japan.
Yamashita
Kentaro
K
Hayashi
Shin-ichiro
S
Yoshimura
Shin-ichi
S
Nakashima
Shigeru
S
Iwama
Toru
T
D000208:Acute Disease; D042683:Angiopoietin-1 / Q000032:analysis; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001929:Brain Edema / Q000188:drug therapy*; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy*; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects; D053491:Proteinase Inhibitory Proteins, Secretory / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*
D042683:Angiopoietin-1; D053491:Proteinase Inhibitory Proteins, Secretory; D013449:Sulfonamides; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine