Abstract
BackgroundTo improve the clinical outcome of patients who suffered ischemic stroke, cerebral ischemia-reperfusion (I/R) injury is one of the major concerns that should be conquered. Inflammatory reactions are considered a major contributor to brain injury following cerebral ischemia, and I/R exacerbates these reactions. The aim of this study was to investigate the possible ameliorative effects of progranulin (PGRN) against I/R injury in mice.MethodsIn vivo I/R was induced in four-week-old male ddY mice by 2 h of MCAO (middle cerebral artery occlusion) followed by 22 h of reperfusion. We evaluate expression of PGRN in I/R brain, efficacy of recombinant-PGRN (r-PGRN) treatment and its therapeutic time-window on I/R injury. Two hours after MCAO, 1.0 ng of r-PRGN or PBS was administered via intracerebroventricular. We assess neutrophil infiltration, expression of tumor necrosis factor (TNF)-α, matrix metalloproteinase-9 (MMP-9) and phosphorylation of nuclear factor-κB (NF-κB) by immunofluorescense staining and Western blotting. We also investigate neutrophil chemotaxis and intercellular adhesion molecule-1 (ICAM-1) expression in vitro inflammation models using isolated neutrophils and endothelial cells.ResultsWe found that expression of PGRN was decreased in the I/R mouse brain. r-PGRN treatment at 2 h after MCAO resulted in a reduction in the infarct volume and decreased brain swelling; this led to an improvement in neurological scores and to a reduction of mortality rate at 24 h and 7 d after MCAO, respectively. Immunohistochemistry, Western blotting, and gelatin zymography also confirmed that r-PGRN treatment suppressed neutrophil recruitment into the I/R brain, and this led to a reduction of NF-κB and MMP-9 activation. In the in vitro inflammation models, PGRN suppressed both the neutrophil chemotaxis and ICAM-1 expression caused by TNF-α in endothelial cells.ConclusionsPGRN exerted ameliorative effects against I/R-induced inflammation, and these effects may be due to the inhibition of neutrophil recruitment into the I/R brain.
Highlights
Stroke is a devastating disease and a leading cause of death and severe disability worldwide [1]
Expression of PGRN in the ischemia-reperfusion brain First, we examined the expression levels of PGRN in I/R brain at 24 h after the induction of focal cerebral ischemia
In the I/R brain, a 60% decrease in PGRN expression was observed compared to the sham contralateral, nonischemic brain, 24 h after middle cerebral artery occlusion (MCAO) (Figure 1A,B; P
Summary
Stroke is a devastating disease and a leading cause of death and severe disability worldwide [1]. And clinically, proinflammatory mediators, such as tumor necrosis factor (TNF)-α, are rapidly released from injured tissue in the acute phase of cerebral ischemia [4,5]; this induces the recruitment and activation of inflammatory cells, including various types of leukocytes [6,7]. This is one of the key features of the neuroimmunological reaction to cerebral ischemia [2,8]. The aim of this study was to investigate the possible ameliorative effects of progranulin (PGRN) against I/R injury in mice
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