Neutrophil elastase inhibitor prevents ischemic brain damage via reduction of vasogenic edema

Abstract

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.

Neutrophil elastase mediates acute pathogenesis and is a determinant of long-term behavioral recovery after traumatic injury to the immature brain

“…Neutrophils, and neutrophil-derived NE in particular, have been implicated in edema formation in the ischemic brain (Stowe et al, 2009; Ikegame et al, 2010). We therefore examined the effect of genetic deficiency of NE on vasogenic edema in the immature injured brain.…”

“…Consistent with our results, treatment with the same NE inhibitor at 0 and 4 h during reperfusion after transient middle cerebral artery occlusion in mice reduced infarct volume, BBB disruption and edema by 24 h (Stowe et al, 2009). Other inhibitors of NE (ONO-5046 or sivelestat) have also shown efficacy at reducing neuronal loss, edema and vascular permeability after focal ischemia in rats or rabbits (Shimakura et al, 2000; Matayoshi et al, 2009; Ikegame et al, 2010). …”

“…That is, specific targeting of NE by genetic deletion or pharmacological inhibition is acutely neuroprotective in rodent and rabbit models of transient focal ischemia (Shimakura et al, 2000; Matayoshi et al, 2009; Stowe et al, 2009; Ikegame et al, 2010), as well as traumatic and ischemic spinal cord injury (Tonai et al, 2001; Iwamoto et al, 2009). This is the first study to define the role of NE in the unique setting of the developing brain, where injury produces an age-specific pro-inflammatory state superimposed on an environment that is rapidly undergoing both structural and behavioral maturation.…”

Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke

“…This observation is supported by findings in pharmacologic and transgenic mice models of neutrophil inhibition. 40,41 In a therapeutic setting, neutralization of IL-17A even 3 hours after stroke resulted in diminished neutrophil infiltration and in a better neurologic outcome in mice. Thus, IL-17A provides an ideal target because its main appearance in stroke is short-lived and has, to our knowledge, only proinflammatory effects.…”

High-Density Lipoproteins in Stroke

“…Using an in vitro model of BBB (Weksler et al 2005), we have recently reported that HDLs could limit the deleterious, elastase-mediated role of activated neutrophils under oxygen-glucose deprivation conditions leading to BBB disruption (Bao . In stroke, inhibition of neutrophil elastase may be a therapeutic target, as shown by using specific inhibitors (Ikegame et al 2010). …”