Inhibition of Matrix metalloproteinase-9 Attenuated Neural Progenitor Cell Migration After Photothrombotic Ischemia

Brain Res. 2008 Sep 4;1228:20-6. doi: 10.1016/j.brainres.2008.06.056. Epub 2008 Jun 24.


Recent studies have shown that neuroblasts migrate from the subventricular zone (SVZ) into the injured area after ischemic brain insults. However, it is not well understood which mechanism mediates this ectopic migration and which types of cells migrate into the damaged region from the SVZ. The present study was designed to investigate the characteristics of the migration of nestin-positive neural stem cells toward the region of ischemic injury after focal cortical ischemia. Nestin-eGFP transgenic mice were used to effectively model the migration of SVZ cells. Photothrombotic ischemia was induced by injection of rose bengal (30 mg/kg) and exposure to cold light. Migration of nestin-positive cells was examined using 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) and bromodeoxyuridine (BrdU) labeling. The number of nestin-positive cells was increased significantly in the peri-infarct area at 5 and 7 days after photothrombosis. A subset of nestin-positive cells was co-labeled with DiI or BrdU. Some of the nestin-positive cells co-expressed doublecortin (DCX) and only a few nestin-positive cells co-labeled with anti-epidermal growth factor receptor (EGFr) antibody. However, no nestin-positive cells were immunoreactive for glial fibrillary acidic protein (GFAP). The inhibition of matrix metalloproteinases (MMPs) using the MMP inhibitor, FN-439, decreased nestin-positive cells in the peri-infarct region at 7 days after photothrombosis. Although MMP-9 was not co-expressed in the nestin-positive cells in the peri-infarct cortex, MMP-9 did co-localize with GFAP-positive astrocytes. These results suggest that nestin-positive neural progenitor cells migrate into the peri-infarct cortex after photothrombotic ischemia and that MMP-9 is involved in the migration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Infarction / metabolism
  • Brain Infarction / physiopathology
  • Brain Ischemia / metabolism
  • Brain Ischemia / physiopathology*
  • Bromodeoxyuridine / chemistry
  • Bromodeoxyuridine / metabolism
  • Carbocyanines / chemistry
  • Carbocyanines / metabolism
  • Cell Movement / drug effects*
  • ErbB Receptors / metabolism
  • Glial Fibrillary Acidic Protein / metabolism
  • Green Fluorescent Proteins / genetics
  • Hydroxamic Acids / administration & dosage
  • Hydroxamic Acids / pharmacology*
  • Immunohistochemistry
  • Intermediate Filament Proteins / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors*
  • Mice
  • Mice, Transgenic
  • Microinjections
  • Microtubule-Associated Proteins / metabolism
  • Nerve Tissue Proteins / genetics
  • Nestin
  • Neuroglia / drug effects
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuropeptides / metabolism
  • Oligopeptides / administration & dosage
  • Oligopeptides / pharmacology*
  • Rose Bengal / chemistry
  • Rose Bengal / metabolism
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stem Cells / metabolism


  • 4-aminobenzoyl-glycyl-prolyl-leucyl-alanine hydroxamic acid
  • Carbocyanines
  • Glial Fibrillary Acidic Protein
  • Hydroxamic Acids
  • Intermediate Filament Proteins
  • Matrix Metalloproteinase Inhibitors
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Nes protein, mouse
  • Nestin
  • Neuropeptides
  • Oligopeptides
  • doublecortin protein
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Rose Bengal
  • 3,3'-dioctadecylindocarbocyanine
  • ErbB Receptors
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse
  • Bromodeoxyuridine