Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis

Matrix metalloproteinases (MMPs) are a family of Zn2+-dependent endopeptida ses targeting extracellular matrix (ECM) compounds as well as a number of o ther proteins. Their proteolytic activity acts as an effector mechanism of tissue remodeling in physiologic and pathologic conditions, and as modulato r of inflammation. In the context of neuro-inflammatory diseases, MMPs have been implicated in processes such as (a) blood-brain barrier (BBB) and blo od-nerve barrier opening, (b) invasion of neural tissue by blood-derived im mune cells, (c) shedding of cytokines and cytokine receptors, and (d) direc t cellular damage in diseases of the peripheral and central nervous system. This review focuses on the role of MMPs in multiple sclerosis (MS) and bac terial meningitis (BM), two neuro-inflammatory diseases where current thera peutic approaches are insufficient to prevent severe disability in the majo rity of patients. Inhibition of enzymatic activity may prevent MMP-mediated neuronal damage due to an overactive or deviated immune response in both d iseases. Downregulation of MMP release may be the molecular basis for the b eneficial effect of IFN-beta and steroids in MS. Instead, synthetic MMP inh ibitors offer the possibility to shut off enzymatic activity of already act ivated MMPs. In animal models of MS and BM, they efficiently attenuated cli nical disease symptoms and prevented brain damage due to excessive metallop roteinase activity. However, the required target profile for the therapeuti c use of this novel group of compounds in human disease is not yet sufficie ntly defined and may be different depending on the type and stage of diseas e. Currently available MMP inhibitors show little target-specificity within the MMP family and may lead to side-effects due to interference with physi ological 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 fu ture. (C) 2001 Elsevier Science BY All rights reserved.