title: The growth factor progranulin attenuates neuronal injury induced by cerebral ischemia-reperfusion through the suppression of neutrophil recruitment.
abstract: BACKGROUND
  To 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.
  
  
  METHODS
  In 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  PGRN 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.
authors: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors: Yusuke
authors: Y
authors: Egashira
authors: Yukiya
authors: Y
authors: Suzuki
authors: Yukio
authors: Y
authors: Azuma
authors: Toshinori
authors: T
authors: Takagi
authors: Keisuke
authors: K
authors: Mishiro
authors: Sou
authors: S
authors: Sugitani
authors: Kazuhiro
authors: K
authors: Tsuruma
authors: Masamitsu
authors: M
authors: Shimazawa
authors: Shinichi
authors: S
authors: Yoshimura
authors: Masanori
authors: M
authors: Kashimata
authors: Toru
authors: T
authors: Iwama
authors: Hideaki
authors: H
authors: Hara
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002469:Cell Separation; D002544:Cerebral Infarction / Q000188:drug therapy / Q000473:pathology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D000077155:Granulins; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000627:therapeutic use*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D009422:Nervous System Diseases / Q000209:etiology / Q000523:psychology; D020556:Neutrophil Infiltration / Q000187:drug effects*; D000077153:Progranulins; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D000077153:Progranulins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D020780:Matrix Metalloproteinase 9
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