Increased MMP-9 and TIMP-1 in mouse neonatal brain and plasma and in human neonatal plasma after hypoxia-ischemia: a potential marker of neonatal encephalopathy

Pediatr Res. 2012 Jan;71(1):63-70. doi: 10.1038/pr.2011.3.


Introduction: To implement neuroprotective strategies in newborns, sensitive and specific biomarkers are needed for identifying those who are at risk for brain damage. We evaluated the effectiveness of matrix metalloproteinases (MMPs) and their naturally occurring tissue inhibitors of metalloproteinases (TIMPs) in predicting neonatal encephalopathy (NE) damage in newborns.

Results: Plasma MMP-9 and TIMP-1 levels were upregulated as early as 1 h after the HI insult but not did not show such elevations after other types of injury (ibotenate-induced excitotoxicity, hypoxia, lipopolysaccharide-induced inflammation), and brain levels reflected this increase soon thereafter. We confirmed these results by carrying out plasma MMP-9 and TIMP-1 measurements in human newborns with NE. In these infants, protein levels of MMP-9 and TIMP-1 were found to be elevated during a short window up to 6 h after birth.

Discussion: This feature is particularly useful in identifying newborns in need of neuroprotection. A second peak observed 72 h after birth is possibly related to the second phase of energy failure after a HI insult. Our data, although preliminary, support the use of MMP-9 and TIMP-1 as early biomarkers for the presence and extent of perinatal brain injury in human term newborns.

Methods: We first used a mouse model of neonatal HI injury to explore mechanistic aspects such as the time course of these markers after the hypoxia-ischemia event, and the correlation between the levels of these candidate markers in brain and plasma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Biomarkers / metabolism*
  • Brain* / metabolism
  • Brain* / pathology
  • Female
  • Gestational Age
  • Humans
  • Hypoxia-Ischemia, Brain* / pathology
  • Hypoxia-Ischemia, Brain* / physiopathology
  • Infant, Newborn
  • Infant, Newborn, Diseases* / pathology
  • Infant, Newborn, Diseases* / physiopathology
  • Male
  • Matrix Metalloproteinase 9 / blood*
  • Mice
  • Mice, Inbred C57BL
  • Tissue Inhibitor of Metalloproteinase-1 / blood*


  • Biomarkers
  • Tissue Inhibitor of Metalloproteinase-1
  • Matrix Metalloproteinase 9