Matrix metalloproteinases and their inhibitors in brain injury and repair

Ariel Miller, Sarah Shapiro, Nitza Lahat and Yanina Galboiz

Matrix metalloproteinases (MMPs), a family of zinc-dependent proteolytic enzymes, together with their endogenous tissue inhibitors, TIMPs, are involved in remodeling of the extracellular matrix (ECM) under a variety of physiological conditions. Recent studies, however, have implicated MMPs in various pathological conditions such as tumor invasion and metastasis, arteriosclerosis, and inflammatory and autoimmune diseases.

MMPs appear to play a key role in the patho-genesis of central nervous system (CNS) disorders, contributing to blood-brain barrier (BBB) eruption, brain edema, immune cell infiltration, myelin degradation and glial-scar formation. Increased activity of MMPs has recently been reported in experimental animal models of demyelinating diseases as well as in multiple sclerosis (MS) patients. Similarly, increased levels of MMPs, and in particular MMP-2 and -9, have been detected in experimental cerebral ischemia as well as in stroke patients. Modulation of MMP/TIMP profiles seems to be associated also with bacterial and viral meningoencephalitis. Additionally, though results are still controversial, MMPs seem to be involved in the deposition of p-amyloid protein in Alzheimer's diseases (AD).

The association of MMPs with CNS disorders has raised considerable interest, as they may represent potential biomarkers for disease activity as well as attractive targets for novel therapeutic strategies, aimed at inhibiting MMP activity. Thus, understanding the structure and function of these key enzymes may have significant implications for arresting evolving brain injury and promoting CNS repair.

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