Metzincin proteases and their inhibitors: foes or friends in nervous system physiology?

Members of the metzincin family of metalloproteinases have long been considered merely degradative enzymes for extracellular matrix molecules. Recently, however, there has been growing appreciation for these proteinases and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs), as fine modulators of nervous system physiology and pathology. Present all along the phylogenetic tree, in all neural cell types, from the nucleus to the synapse and in the extracellular space, metalloproteinases exhibit a complex spatiotemporal profile of expression in the nervous parenchyma and at the neurovascular interface. The irreversibility of their proteolytic activity on numerous biofactors (e.g., growth factors, cytokines, receptors, DNA repair enzymes, matrix proteins) is ideally suited to sustain structural changes that are involved in physiological or postlesion remodeling of neural networks, learning consolidation or impairment, neurodegenerative and neuroinflammatory processes, or progression of malignant gliomas. The present review provides a state of the art overview of the involvement of the metzincin/TIMP system in these processes and the prospects of new therapeutic strategies based on the control of metalloproteinase activity.