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Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis
D Leppert1, R L Lindberg, L Kappos
1Department of Neurology, University Hospitals, Petersgraben 4, CH-4031, Basel, Switzerland. David.Leppert@unibas.ch
Abstract:
Matrix metalloproteinases (MMPs) are a family of Zn2+-dependent endopeptidases targeting extracellular matrix (ECM) compounds as well as a number of other proteins. Their proteolytic activity acts as an effector mechanism of tissue remodeling in physiologic and pathologic conditions, and as modulator of inflammation. In the context of neuro-inflammatory diseases, MMPs have been implicated in processes such as (a) blood-brain barrier (BBB) and blood-nerve barrier opening, (b) invasion of neural tissue by blood-derived immune cells, (c) shedding of cytokines and cytokine receptors, and (d) direct cellular damage in diseases of the peripheral and central nervous system. This review focuses on the role of MMPs in multiple sclerosis (MS) and bacterial meningitis (BM), two neuro-inflammatory diseases where current therapeutic approaches are insufficient to prevent severe disability in the majority of patients. Inhibition of enzymatic activity may prevent MMP-mediated neuronal damage due to an overactive or deviated immune response in both diseases. Downregulation of MMP release may be the molecular basis for the beneficial effect of IFN-beta and steroids in MS. Instead, synthetic MMP inhibitors offer the possibility to shut off enzymatic activity of already activated MMPs. In animal models of MS and BM, they efficiently attenuated clinical disease symptoms and prevented brain damage due to excessive metalloproteinase activity. However, the required target profile for the therapeutic use of this novel group of compounds in human disease is not yet sufficiently defined and may be different depending on the type and stage of disease. Currently available MMP inhibitors show little target-specificity within the MMP family and may lead to side-effects due to interference with physiological functions of MMPs. Results from human MS and BM indicate that only a restricted number of MMPs specific for each disease is up-regulated. MMP inhibitors with selective target profiles offer the possibility of a more efficient therapy of MS and BM and may enter clinical trials in the near future.
Insights
Matrix metalloproteinases (MMPs) play a key role in neuroinflammatory diseases like multiple sclerosis (MS) and bacterial meningitis (BM). Inhibiting MMPs shows promise for treating these conditions, but selective inhibitors are needed for safe and effective therapies.
Area of Science:
- Neuroimmunology
- Molecular Biology
- Pharmacology
Background:
- Matrix metalloproteinases (MMPs) are enzymes involved in tissue remodeling and inflammation.
- MMPs contribute to neuroinflammation by breaching barriers, facilitating immune cell invasion, and causing direct cellular damage in the central and peripheral nervous systems.
Purpose of the Study:
- To review the role of MMPs in multiple sclerosis (MS) and bacterial meningitis (BM).
- To explore the therapeutic potential of MMP inhibitors in these neuroinflammatory diseases.
Main Methods:
- Literature review focusing on MMPs in MS and BM.
- Analysis of preclinical data from animal models of MS and BM.
- Discussion of current and potential therapeutic strategies involving MMP inhibition.
Main Results:
- MMPs are implicated in the pathogenesis of MS and BM, contributing to neuronal damage.
- MMP inhibitors have shown efficacy in attenuating disease symptoms and preventing brain damage in animal models.
- Current MMP inhibitors lack specificity, potentially causing side effects due to interference with physiological MMP functions.
Conclusions:
- Targeted inhibition of specific MMPs offers a promising therapeutic avenue for MS and BM.
- Development of selective MMP inhibitors is crucial for effective and safe treatment of neuroinflammatory conditions.
- Further research is needed to define optimal therapeutic targets and profiles for MMP inhibitors in human diseases.