Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage.
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.
Wang
Jian
J
Department of Pharmacological Sciences, University Medical Center at Stony Brook, Stony Brook, NY 11794-8651, USA.
Tsirka
Stella E
SE
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000201:enzymology* / Q000378:metabolism; D001930:Brain Injuries / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D016923:Cell Death / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D004151:Dipeptides / Q000627:therapeutic use*; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000201:enzymology; D005455:Fluorescent Antibody Technique; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009474:Neurons / Q000201:enzymology; D018384:Oxidative Stress; D011480:Protease Inhibitors / Q000627:therapeutic use*
D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D020780:Matrix Metalloproteinase 9