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Brain Advance Access published online on March 30, 2005
Brain, doi:10.1093/brain/awh489
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© The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received December 10, 2004
Revised February 24, 2005
Accepted February 25, 2005

Article

Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage

Jian Wang 1 and Stella E. Tsirka 1*

1 Department of Pharmacological Sciences, University Medical Center at Stony Brook, Stony Brook, NY, USA

* To whom correspondence should be addressed.
Stella E. Tsirka, E-mail: stella{at}pharm.sunysb.edu


  Abstract

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.

Keywords: intracerebral haemorrhage; stroke; matrix metalloproteinase; neutrophil; reactive oxygen species; mouse.
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