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 Citations (Scopus)

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

Fingerprint

Metalloproteases
Reperfusion
Matrix Metalloproteinases
Wounds and Injuries
Ischemia
Matrix Metalloproteinase 9
Reperfusion Injury
Neuroglia
glycylproline
Collagen
Neurons
Matrix Metalloproteinase Inhibitors
Middle Cerebral Artery Infarction
Matrix Metalloproteinase 2
Microvessels
Basement Membrane
Cerebral Cortex
Sutures
Endothelial Cells
Gels

Keywords

  • Brain damage
  • Cerebral ischemia
  • Neuroprotection
  • Rats

ASJC Scopus subject areas

  • Neurology
  • Neuroscience(all)

Cite this

Lu, A., Clark, J. F., Broderick, J. P., Pyne-Geithman, G. J., Wagner, K. R., Ran, R., ... 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

Reperfusion activates metalloproteinases that contribute to neurovascular injury. / Lu, Aigang; Clark, Joseph F.; Broderick, Joseph P.; Pyne-Geithman, Gail J.; Wagner, Kenneth R.; Ran, Ruiqiong; Khatri, Pooja; Tomsick, Thomas; Sharp, Frank R.

In: Experimental Neurology, Vol. 210, No. 2, 04.2008, p. 549-559.

Research output: Contribution to journalArticle

Lu, A, Clark, JF, Broderick, JP, Pyne-Geithman, GJ, Wagner, KR, Ran, R, Khatri, P, Tomsick, T & Sharp, FR 2008, 'Reperfusion activates metalloproteinases that contribute to neurovascular injury', Experimental Neurology, vol. 210, no. 2, pp. 549-559. https://doi.org/10.1016/j.expneurol.2007.12.003
Lu A, Clark JF, Broderick JP, Pyne-Geithman GJ, Wagner KR, Ran R et al. Reperfusion activates metalloproteinases that contribute to neurovascular injury. Experimental Neurology. 2008 Apr;210(2):549-559. https://doi.org/10.1016/j.expneurol.2007.12.003
Lu, Aigang ; Clark, Joseph F. ; Broderick, Joseph P. ; Pyne-Geithman, Gail J. ; Wagner, Kenneth R. ; Ran, Ruiqiong ; Khatri, Pooja ; Tomsick, Thomas ; Sharp, Frank R. / Reperfusion activates metalloproteinases that contribute to neurovascular injury. In: Experimental Neurology. 2008 ; Vol. 210, No. 2. pp. 549-559.
@article{dd28f399b63f479a8e1007a76e15322a,
title = "Reperfusion activates metalloproteinases that contribute to neurovascular injury",
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.",
keywords = "Brain damage, Cerebral ischemia, Neuroprotection, Rats",
author = "Aigang Lu and Clark, {Joseph F.} and Broderick, {Joseph P.} and Pyne-Geithman, {Gail J.} and Wagner, {Kenneth R.} and Ruiqiong Ran and Pooja Khatri and Thomas Tomsick and Sharp, {Frank R}",
year = "2008",
month = "4",
doi = "10.1016/j.expneurol.2007.12.003",
language = "English (US)",
volume = "210",
pages = "549--559",
journal = "Experimental Neurology",
issn = "0014-4886",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Reperfusion activates metalloproteinases that contribute to neurovascular injury

AU - Lu, Aigang

AU - Clark, Joseph F.

AU - Broderick, Joseph P.

AU - Pyne-Geithman, Gail J.

AU - Wagner, Kenneth R.

AU - Ran, Ruiqiong

AU - Khatri, Pooja

AU - Tomsick, Thomas

AU - Sharp, Frank R

PY - 2008/4

Y1 - 2008/4

N2 - 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.

AB - 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.

KW - Brain damage

KW - Cerebral ischemia

KW - Neuroprotection

KW - Rats

UR - http://www.scopus.com/inward/record.url?scp=41149138828&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=41149138828&partnerID=8YFLogxK

U2 - 10.1016/j.expneurol.2007.12.003

DO - 10.1016/j.expneurol.2007.12.003

M3 - Article

C2 - 18187134

AN - SCOPUS:41149138828

VL - 210

SP - 549

EP - 559

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

IS - 2

ER -