Reperfusion activates metalloproteinases that contribute to neurovascular injury

Aigang Lu, Joseph F. Clark, Joseph P. Broderick, Gail J. Pyne-Geithman, Kenneth R. Wagner, Ruiqiong Ran, Pooja Khatri, Thomas Tomsick, Frank R Sharp

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

In this study, we examine the effects of reperfusion on the activation of matrix metalloproteinase (MMP) and assess the relationship between MMP activation during reperfusion and neurovascular injury. Ischemia was produced using suture-induced middle cerebral artery occlusion in rats. The MMP activation was examined with in situ and gel zymography. Injury to cerebral endothelial cells and basal lamina was assessed using endothelial barrier antigen (EBA) and collagen IV immunohistochemistry. Injury to neurons and glial cells was assessed using Cresyl violet staining. These were examined at 3 h after reperfusion (8 h after initiation of ischemia) and compared with permanent ischemia at the same time points to assess the effects of reperfusion. A broad-spectrum MMP inhibitor, AHA (p-aminobenzoyl-Gly-Pro-d-Leu-d-Ala-hydroxamate, 50 mg/kg intravenously) was administered 30 min before reperfusion to assess the roles of MMPs in activating gelatinolytic enzymes and in reperfusion-induced injury. We found that reperfusion accelerated and potentiated MMP-9 and MMP-2 activation and injury to EBA and collagen IV immunopositive microvasculature and to neurons and glial cells in ischemic cortex and striatum relative to permanent ischemia. Administering AHA 30 min before reperfusion decreased MMP-9 activation and neurovascular injury in ischemic cerebral cortex.

Original languageEnglish (US)
Pages (from-to)549-559
Number of pages11
JournalExperimental Neurology
Volume210
Issue number2
DOIs
StatePublished - Apr 2008

Keywords

  • Brain damage
  • Cerebral ischemia
  • Neuroprotection
  • Rats

ASJC Scopus subject areas

  • Neurology
  • Neuroscience(all)

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    Lu, A., Clark, J. F., Broderick, J. P., Pyne-Geithman, G. J., Wagner, K. R., Ran, R., Khatri, P., Tomsick, T., & Sharp, F. R. (2008). Reperfusion activates metalloproteinases that contribute to neurovascular injury. Experimental Neurology, 210(2), 549-559. https://doi.org/10.1016/j.expneurol.2007.12.003