Brain Advance Access originally published online on March 30, 2005
Brain 2005 128(7):1622-1633; doi:10.1093/brain/awh489
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage
Department of Pharmacological Sciences, University Medical Center at Stony Brook, Stony Brook, NY, USA
Correspondence to: Stella E. Tsirka, PhD, Department of Pharmacological Sciences, University Medical Center at Stony Brook, Stony Brook, NY 11794-8651, USA E-mail: stella{at}pharm.sunysb.edu
Intracerebral haemorrhage (ICH) is an acute neurological disorder without effective treatment. Mechanisms of acute brain injury after ICH remain to be clarified. Although a few studies suggested a detrimental role for the gelatinase matrix metalloproteinase (MMP)-9 in ICH, the relationship between MMP-9 activity and acute brain injury after ICH is not determined. In this study, we first examined the expression of gelatinases in vivo using a collagenase-induced mouse model of ICH. Gel zymography revealed that MMP-9 was activated and upregulated after ICH. In situ zymography showed that gelatinase activity was mostly co-localized with neurons and endothelial cells of the blood vessel matrix. Inhibition with a broad-spectrum metalloproteinase inhibitor GM6001 (100 mg/kg) ameliorated dysregulated gelatinase activity, neutrophil infiltration, production of oxidative stress, brain oedema and degenerating neurons. Functional improvement and a decrease in injury volume were also observed. We provide evidence that MMP-9 may play a deleterious role in acute brain injury within the first 3 days after ICH. Blockade of MMP activity during this critical period may have efficacy as a therapeutic strategy for the treatment of acute brain injury after ICH.
Key Words: intracerebral haemorrhage; stroke; matrix metalloproteinase; neutrophil; reactive oxygen species; mouse
Abbreviations: BBB = blood–brain barrier; ICH = intracerebral haemorrhage; MMP = matrix metalloproteinase; ROS = reactive oxygen species
Received December 10, 2004. Revised February 24, 2005. Accepted February 25, 2005.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Xue, Y. Fan, S. Liu, D. A. Zygun, A. Demchuk, and V. W. Yong Contributions of multiple proteases to neurotoxicity in a mouse model of intracerebral haemorrhage Brain, September 4, 2008; (2008) awn215v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Z. Lee, Z. Xue, Y. Zhu, G.-Y. Yang, and W. L. Young Matrix Metalloproteinase-9 Inhibition Attenuates Vascular Endothelial Growth Factor-Induced Intracerebral Hemorrhage Stroke, September 1, 2007; 38(9): 2563 - 2568. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wang and S. Dore Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage Brain, June 1, 2007; 130(6): 1643 - 1652. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Liu and P. J. Hornsby Senescent Human Fibroblasts Increase the Early Growth of Xenograft Tumors via Matrix Metalloproteinase Secretion Cancer Res., April 1, 2007; 67(7): 3117 - 3126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Song, S. Ge, and J. S. Pachter Caveolin-1 regulates expression of junction-associated proteins in brain microvascular endothelial cells Blood, February 15, 2007; 109(4): 1515 - 1523. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Xue, M. D. Hollenberg, and V. Wee Yong Combination of Thrombin and Matrix Metalloproteinase-9 Exacerbates Neurotoxicity in Cell Culture and Intracerebral Hemorrhage in Mice J. Neurosci., October 4, 2006; 26(40): 10281 - 10291. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Bruno and A. C. Cuello Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade PNAS, April 25, 2006; 103(17): 6735 - 6740. [Abstract] [Full Text] [PDF]
|
|