Reduction in levels of matrix metalloproteinases and increased expression of tissue inhibitor of metalloproteinase-2 in response to mild hypothermia therapy in experimental stroke

Jongeun Lee, Jung Yoon Yone, Michael E. Moseley, Midori A. Yenari

Research output: Contribution to journalArticle

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Abstract

Object. Mild hypothermia is a robust neuroprotectant, and the results of prospective clinical trials have indicated that it may improve neurological outcome in certain instances. One aspect of this protection has been associated with the prevention of blood-brain barrier (BBB) disruption. Matrix metalloproteinases (MMPs) have been implicated in BBB disruption because they can degrade the extracellular matrix. In this study the authors explored the relationship between hypothermia and MMPs and whether BBB preservation resulting from mild hypothermia therapy is due to alterations in MMP expression. Methods. Rats were subjected to middle cerebral artery occlusion for 2 hours; the animals were maintained in a state of normothermia or mild hypothermia (33°C) immediately after the onset of ischemia. The animals' brains were collected 2, 6, and 24 hours after ischemia began. Contrast-enhanced T 1-weighted magnetic resonance imaging was performed at 24 hours to assess the extent of BBB disruption. Consistent with prior reports, areas of BBB disruption detected on T1-weighted images were smaller in the brains of rats maintained in a state of hypothermia (normothermia group 8.6 ± 3% of the brain; hypothermia group 0.2 ± 0.1% of the brain; p < 0.01). Expression of both MMP-2 and MMP-9 at the transcriptional and translational levels was reduced in hypothermic brains at 6 hours and 24 hours after ischemic injury. Matrix metalloproteinase-9 was primarily localized to cells of monocytic origin but was also observed in neurons and astrocytes. Matrix metalloproteinase-2 was found in some neurons and astrocytes but not in inflammatory cells. In addition, hypothermia increased the levels of the endogenous MMP inhibitor, tissue inhibitor of metalloproteinases-2. Conclusions. The authors conclude that mild hypothermia attenuates BBB disruption, decreases MMP expression, and suppresses MMP activity.

Original languageEnglish
Pages (from-to)289-297
Number of pages9
JournalJournal of Neurosurgery
Volume103
Issue number2
Publication statusPublished - 2005 Aug 1

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Tissue Inhibitor of Metalloproteinase-2
Investigational Therapies
Hypothermia
Matrix Metalloproteinases
Blood-Brain Barrier
Stroke
Brain
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Astrocytes
Ischemia
Neurons
Matrix Metalloproteinase Inhibitors
Middle Cerebral Artery Infarction
Neuroprotective Agents
Extracellular Matrix
Magnetic Resonance Imaging
Clinical Trials
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Surgery
  • Clinical Neurology

Cite this

@article{6ee6684600b44c5d80a73291f6e2d84d,
title = "Reduction in levels of matrix metalloproteinases and increased expression of tissue inhibitor of metalloproteinase-2 in response to mild hypothermia therapy in experimental stroke",
abstract = "Object. Mild hypothermia is a robust neuroprotectant, and the results of prospective clinical trials have indicated that it may improve neurological outcome in certain instances. One aspect of this protection has been associated with the prevention of blood-brain barrier (BBB) disruption. Matrix metalloproteinases (MMPs) have been implicated in BBB disruption because they can degrade the extracellular matrix. In this study the authors explored the relationship between hypothermia and MMPs and whether BBB preservation resulting from mild hypothermia therapy is due to alterations in MMP expression. Methods. Rats were subjected to middle cerebral artery occlusion for 2 hours; the animals were maintained in a state of normothermia or mild hypothermia (33°C) immediately after the onset of ischemia. The animals' brains were collected 2, 6, and 24 hours after ischemia began. Contrast-enhanced T 1-weighted magnetic resonance imaging was performed at 24 hours to assess the extent of BBB disruption. Consistent with prior reports, areas of BBB disruption detected on T1-weighted images were smaller in the brains of rats maintained in a state of hypothermia (normothermia group 8.6 ± 3{\%} of the brain; hypothermia group 0.2 ± 0.1{\%} of the brain; p < 0.01). Expression of both MMP-2 and MMP-9 at the transcriptional and translational levels was reduced in hypothermic brains at 6 hours and 24 hours after ischemic injury. Matrix metalloproteinase-9 was primarily localized to cells of monocytic origin but was also observed in neurons and astrocytes. Matrix metalloproteinase-2 was found in some neurons and astrocytes but not in inflammatory cells. In addition, hypothermia increased the levels of the endogenous MMP inhibitor, tissue inhibitor of metalloproteinases-2. Conclusions. The authors conclude that mild hypothermia attenuates BBB disruption, decreases MMP expression, and suppresses MMP activity.",
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Reduction in levels of matrix metalloproteinases and increased expression of tissue inhibitor of metalloproteinase-2 in response to mild hypothermia therapy in experimental stroke. / Lee, Jongeun; Yone, Jung Yoon; Moseley, Michael E.; Yenari, Midori A.

In: Journal of Neurosurgery, Vol. 103, No. 2, 01.08.2005, p. 289-297.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Reduction in levels of matrix metalloproteinases and increased expression of tissue inhibitor of metalloproteinase-2 in response to mild hypothermia therapy in experimental stroke

AU - Lee, Jongeun

AU - Yone, Jung Yoon

AU - Moseley, Michael E.

AU - Yenari, Midori A.

PY - 2005/8/1

Y1 - 2005/8/1

N2 - Object. Mild hypothermia is a robust neuroprotectant, and the results of prospective clinical trials have indicated that it may improve neurological outcome in certain instances. One aspect of this protection has been associated with the prevention of blood-brain barrier (BBB) disruption. Matrix metalloproteinases (MMPs) have been implicated in BBB disruption because they can degrade the extracellular matrix. In this study the authors explored the relationship between hypothermia and MMPs and whether BBB preservation resulting from mild hypothermia therapy is due to alterations in MMP expression. Methods. Rats were subjected to middle cerebral artery occlusion for 2 hours; the animals were maintained in a state of normothermia or mild hypothermia (33°C) immediately after the onset of ischemia. The animals' brains were collected 2, 6, and 24 hours after ischemia began. Contrast-enhanced T 1-weighted magnetic resonance imaging was performed at 24 hours to assess the extent of BBB disruption. Consistent with prior reports, areas of BBB disruption detected on T1-weighted images were smaller in the brains of rats maintained in a state of hypothermia (normothermia group 8.6 ± 3% of the brain; hypothermia group 0.2 ± 0.1% of the brain; p < 0.01). Expression of both MMP-2 and MMP-9 at the transcriptional and translational levels was reduced in hypothermic brains at 6 hours and 24 hours after ischemic injury. Matrix metalloproteinase-9 was primarily localized to cells of monocytic origin but was also observed in neurons and astrocytes. Matrix metalloproteinase-2 was found in some neurons and astrocytes but not in inflammatory cells. In addition, hypothermia increased the levels of the endogenous MMP inhibitor, tissue inhibitor of metalloproteinases-2. Conclusions. The authors conclude that mild hypothermia attenuates BBB disruption, decreases MMP expression, and suppresses MMP activity.

AB - Object. Mild hypothermia is a robust neuroprotectant, and the results of prospective clinical trials have indicated that it may improve neurological outcome in certain instances. One aspect of this protection has been associated with the prevention of blood-brain barrier (BBB) disruption. Matrix metalloproteinases (MMPs) have been implicated in BBB disruption because they can degrade the extracellular matrix. In this study the authors explored the relationship between hypothermia and MMPs and whether BBB preservation resulting from mild hypothermia therapy is due to alterations in MMP expression. Methods. Rats were subjected to middle cerebral artery occlusion for 2 hours; the animals were maintained in a state of normothermia or mild hypothermia (33°C) immediately after the onset of ischemia. The animals' brains were collected 2, 6, and 24 hours after ischemia began. Contrast-enhanced T 1-weighted magnetic resonance imaging was performed at 24 hours to assess the extent of BBB disruption. Consistent with prior reports, areas of BBB disruption detected on T1-weighted images were smaller in the brains of rats maintained in a state of hypothermia (normothermia group 8.6 ± 3% of the brain; hypothermia group 0.2 ± 0.1% of the brain; p < 0.01). Expression of both MMP-2 and MMP-9 at the transcriptional and translational levels was reduced in hypothermic brains at 6 hours and 24 hours after ischemic injury. Matrix metalloproteinase-9 was primarily localized to cells of monocytic origin but was also observed in neurons and astrocytes. Matrix metalloproteinase-2 was found in some neurons and astrocytes but not in inflammatory cells. In addition, hypothermia increased the levels of the endogenous MMP inhibitor, tissue inhibitor of metalloproteinases-2. Conclusions. The authors conclude that mild hypothermia attenuates BBB disruption, decreases MMP expression, and suppresses MMP activity.

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