Published Online
on May 11, 2006

A more recent version of this article appeared on June 1, 2006

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Submitted on January 27, 2006
Revised on March 21, 2006
Accepted on March 27, 2006

Increased Brain Expression of Matrix Metalloproteinase-9 After Ischemic and Hemorrhagic Human Stroke

Anna Rosell PhD; Arantxa Ortega-Aznar MD; José Alvarez-Sabín MD, PhD; Israel Fernández-Cadenas MSc; Marc Ribó MD, PhD; Carlos A. Molina MD, PhD; Eng H. Lo PhD; and Joan Montaner MD, PhD^*

From the Neurovascular Research Laboratory (A.R., J.A.-S., I.F.-C., M.R., C.A.M., J.M.), Neurovascular Unit, Department of Neurology of Vall d’Hebron University Hospital, Department of Internal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; the Neuropathology Unit (A.O.-A), Department of Pathology; Vall d’Hebron University Hospital, Barcelona, Spain; and the Neuroprotection Research Laboratory (E.H.L.), Departments of Neurology and Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: 31862jmv{at}comb.es.

Background and Purpose--Abnormal expression of some matrix metalloproteinases (MMP) has shown to play a deleterious role in brain injury in experimental models of cerebral ischemia. We aimed to investigate MMP-2 (gelatinase A) and MMP-9 (gelatinase B) in brain parenchyma in both ischemic and hemorrhagic strokes.

Methods--Postmortem fresh brain tissue from 6 ischemic and 8 hemorrhagic stroke patients was obtained within the first 6 hours after death. Finally, 78 brain tissue samples from different areas (infarct, peri-infarct, perihematoma and contralateral hemisphere) were studied. To quantify gelatinase content we performed gelatin zymograms that were confirmed by Western Blot Analysis, immunohistochemistry to localize MMP source, and in situ zymography to detect gelatinase activity.

Results--Among ischemic cases, gelatin zymography showed increased MMP-9 content in infarct core although peri-infarct tissue presented also higher levels than contralateral hemisphere (P<0.0001 and P=0.042, respectively). Within infarct core, MMP-9 was mainly located around blood vessels, associated to neutrophil infiltration and activated microglial cells. In peri-infarct areas the major source of MMP-9 were microglial cells. Tissue around intracranial hemorrhage also displayed higher MMP-9 levels than contralateral hemisphere (P=0.008) in close relationship with glial cells. MMP-2 was constitutively expressed and remained invariable in different brain areas.

Conclusions--Our results demonstrate in situ higher levels of MMP-9 in human brain tissue after ischemic and hemorrhagic stroke, suggesting a contribution of MMP-9 to ischemic brain injury and perihematoma edema.

Key words: MMP-2 • MMP-9 • stroke

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