Matrix Metalloproteinase-9: Dual Role and Temporal Profile in Intracerebral Hemorrhage

• Published in: Journal of stroke and cerebrovascular diseases 2014-11, Vol.23 (10), p.2498-2505
• Main Authors: Chang, Jason J., MD, Emanuel, Benjamin A., DO, Mack, William J., MD, Tsivgoulis, Giorgios, MD, Alexandrov, Andrei V., MD
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; blood brain barrier; Brain Edema - drug therapy; Brain Edema - metabolism; Brain Edema - mortality; Cardiovascular; Cerebral Hemorrhage - complications; Cerebral Hemorrhage - drug therapy; Cerebral Hemorrhage - metabolism; Cerebral Hemorrhage - mortality; Cerebral Hemorrhage - pathology; gelatinase B; Hematoma - drug therapy; Hematoma - metabolism; Hematoma - mortality; Humans; intracerebral hemorrhage; Matrix metalloproteinase; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase Inhibitors - therapeutic use; Neurology; neuroprotection; Neuroprotective Agents - administration & dosage; perihematomal edema; Time Factors
• ISSN: 1052-3057; 1532-8511
• DOI: 10.1016/j.jstrokecerebrovasdis.2014.07.005

Background Clinical outcome after intracerebral hemorrhage (ICH) remains poor. Recent trials in ICH, focusing on hematoma reduction, have not yielded significant clinical improvement. The modulation of matrix metalloproteinase (MMP)-9 may represent a potential therapeutic target for reducing perihematomal edema (PHE) and improving clinical outcome. Methods We searched Cochrane Library, Ovid/Medline, and PubMed databases using combinations of the following MeSH search terms: “intracerebral hemorrhage,” “matrix metalloproteinase,” “minocycline,” “inhibition,” and “neuroprotection”. Results MMP-9 levels in animal models have largely shown detrimental correlations with mortality, clinical outcome, hematoma volume, and PHE. Animal models and clinical studies have established a timeline for MMP-9 expression and corresponding PHE that include an initial peak on days 1-3 and a secondary peak on day 7. Clinical studies evaluating MMP-9 levels in the acute phase (days 1-3) and subacute phase (day 7) of ICH suggest that MMP-9 may be detrimental in the acute phase through destruction of basal lamina, activation of vascular endothelial growth factor, and activation of apoptosis but assist in recovery in the subacute phase through angiogenesis. Conclusions MMP-9 inhibition represents a potentially effective target for neuroprotection in ICH. However, as a ubiquitous protein, the inhibition of pathologic processes must be balanced against the preservation of neuroprotective angiogenesis. As the opposing roles of MMP-9 may have similar mechanisms, the most important factor may be the timing of MMP-9 inhibition. Further studies are necessary to delineate these mechanisms and their temporal relationship.