Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia

J Neurosci. 2007 Feb 14;27(7):1511-8. doi: 10.1523/JNEUROSCI.4391-06.2007.

Abstract

Inhibition of matrix metalloproteinase-9 (MMP-9) protects the adult brain after cerebral ischemia. However, the role of MMP-9 in the immature brain after hypoxia-ischemia (HI) is unknown. We exposed MMP-9(-/-) [MMP-9 knock-out (KO)] and wild-type (WT) mice to HI on postnatal day 9. HI was induced by unilateral ligation of the left carotid artery followed by hypoxia (10% O2; 36 degrees C). Gelatin zymography showed that MMP-9 activity was transiently increased at 24 h after HI in the ipsilateral hemisphere and MMP-9-positive cells were colocalized with activated microglia. Seven days after 50 min of HI, cerebral tissue volume loss was reduced in MMP-9 KO (21.8 +/- 1.7 mm3; n = 22) compared with WT (32.3 +/- 2.1 mm3; n = 22; p < 0.001) pups, and loss of white-matter components was reduced in MMP-9 KO compared with WT pups (neurofilament: WT, 50.9 +/- 5.4%; KO, 18.4 +/- 3.1%; p < 0.0001; myelin basic protein: WT, 57.5 +/- 5.8%; KO, 23.2 +/- 3.5%; p = 0.0001). The neuropathological changes were associated with a delayed and diminished leakage of the blood-brain barrier (BBB) and a decrease in inflammation in MMP-9-deficient animals. In contrast, the neuroprotective effects after HI in MMP-9-deficient animals were not linked to either caspase-dependent (caspase-3 and cytochrome c) or caspase-independent (apoptosis-inducing factor) processes. This study demonstrates that excessive activation of MMP-9 is deleterious to the immature brain, which is associated with the degree of BBB leakage and inflammation. In contrast, apoptosis does not appear to be a major contributing factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis Inducing Factor / metabolism
  • Blood-Brain Barrier / physiopathology
  • Brain Infarction / etiology
  • Brain Infarction / pathology
  • Brain* / growth & development
  • Brain* / metabolism
  • Brain* / pathology
  • Caspase 3 / metabolism
  • Cell Death / physiology
  • Cytochromes c / metabolism
  • Encephalitis / etiology
  • Encephalitis / pathology
  • Gene Expression Regulation, Developmental / genetics*
  • Hypoxia-Ischemia, Brain / metabolism*
  • Hypoxia-Ischemia, Brain / pathology*
  • Hypoxia-Ischemia, Brain / physiopathology
  • Immunohistochemistry / methods
  • Indoles
  • Matrix Metalloproteinase 9 / deficiency*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myelin Basic Protein / metabolism
  • Neurofilament Proteins / metabolism
  • RNA, Messenger / biosynthesis
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Statistics, Nonparametric
  • Time Factors

Substances

  • Apoptosis Inducing Factor
  • Indoles
  • Myelin Basic Protein
  • Neurofilament Proteins
  • RNA, Messenger
  • DAPI
  • Cytochromes c
  • Caspase 3
  • Matrix Metalloproteinase 9