Targeting MMPs in Acute and Chronic Neurological Conditions

Abstract

Summary:The matrix metalloproteinases (MMPs) are important enzymes that regulate developmental processes, maintain normal physiology in adulthood and have reparative roles at specific stages after an insult to the nervous system. Conversely, the concordant presence and significant upregulation of several MMP members in virtually all neurological conditions result in pathology. Thus, the MMPs have diverse functions, capable of mediating repair and recovery on the one hand and being involved in producing injury on the other. Therefore, targeting MMPs in neurological conditions has become a complicated challenge. This article highlights the beneficial roles of MMPs in normal and reparative processes within the nervous system and discusses the detriments of MMPs encountered in pathology. We review the availability of MMP inhibitors for clinical use and propose that an important consideration for these inhibitors is timing and duration of their use. With acute injuries where a massive upregulation of several MMPs are observed in the early periods after the insult, early and short-term use of broad spectrum MMP inhibitors would seem logical. In chronic conditions where recurrent insults to the CNS are accompanied by prolonged upregulation of MMPs, thereby necessitating the chronic use of medications, the beneficial effects of MMPs in repair may be compromised by the long-term application of MMP inhibitors. In this review we have used spinal cord injury and multiple sclerosis as examples of acute and chronic neurological conditions, respectively, and we consider the use of MMP inhibitors in these states.

Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2) Contributes to Secondary Damage after Spinal Cord Injury

“…Inhibition of NAD(P)H redox activity leads to increased MMP-9 (via p38 MAPK and JNK) and reduced MMP-2 (via ERK 1/2). What effect MK2 deficiency may have on other MMPs implicated in SCI (Wells et al, 2003b;Yong et al, 2007) remains unknown.…”

Ephrin-B2-induced Cleavage of EphB2 Receptor Is Mediated by Matrix Metalloproteinases to Trigger Cell Repulsion

“…Here we demonstrate that the EphB2 receptor is cleaved by secreted MMPs, MMP-2 and MMP-9, and this cleavage is induced by ephrinB-EphB receptor interaction. MMP-2 and MMP-9 are the most abundant MMPs in the brain, and their expression/activities are regulated during neural development, in response to brain injury, and in several neurological disorders (14,30). Therefore, changes in the expression and/or activation of MMP-2/MMP-9 may directly regulate EphB2-mediated cellular responses.…”

Serum Levels of Matrix Metalloproteinases: Implications in Clinical Neurology

“…Matrix metalloproteinases (MMPs) represent a multi-member family of zinc-dependent proteases with a wide range of substrates, including extracellular matrix components, cytokines, receptors, and cell motility factors [1,2]. They are recognized as the main proteolytic enzyme group involved in remodeling the extracellular matrix and modifying cell-cell and cell-matrix interactions [3].…”

“…Many different human MMPs have been identified [1]. Based on function and structure, MMPs can be subdivided into 5 groups: (i) collagenases (MMPs-1, -8 and -13); (ii) gelatinases A and B (MMPs-2 and -9); (iii) stromelysins-1 and -2 (MMPs-3 and -10); (iv) a more heterogeneous subgroup containing matrilysin (MMP-7), enamelysin (MMP-20), the mmp 20 gene product, macrophage metalloelastase (MMP-12), and MMP-19 (together making up the ‘classical’ MMPs), and (v) membrane-type MMPs (MT-MMPs-1–4 and stromelysin-3, MMP-11) [4].…”

“…2). Free radicals, serine proteases, and other activated MMPs are among the factors that convert a pro-MMP to its active enzyme [1]. When activated, the MMPs can be inhibited by their tissue inhibitors (TIMPs) [6].…”