Metalloproteinases and their inhibitors as therapeutic targets for multiple sclerosis: current evidence and future perspectives

The treatment of multiple sclerosis (MS) has seen important changes in the last two decades with the introduction of several drugs able to modify the evolution of this disease. Current MS therapies primarily target the peripheral immune response, although it has been suggested that their ef cacy could be in part the result of the bene cial effect on other non- speci c targets, such as matrix metalloproteinases (MMPs). Numerous experimental studies have suggested that MMPs may be involved in MS pathogenesis by contributing to blood–brain barrier disruption, migration of leukocytes into the central nervous system, demyelination and axonal damage. Therefore, MMPs have been considered important therapeutic targets in the course of MS. In this respect, different attempts have been made to develop synthetic, low-molecular-weight inhibitors of MMPs for the potential treatment of diseases in which MMPs play a major role. However, technical dif culties, side effects and reduced patient compliance because of parenteral administration have greatly limited the development in the clinical practice of speci c anti-MMP drugs. By contrast, interesting results have been obtained with compounds that are already used in the clinical practice, such as MS drugs and natural compounds with anti-in ammatory and antioxidant activity. Here, we discuss the evidence and potential mechanisms for altered MMP function in MS. Furthermore, we outline the possible medical implications for the use of compounds that target MMP activity and we propose that together with anti-MS drugs, other compounds with anti-in ammatory and antioxidant properties, such as natural ω3 fatty acids, polyphenols and tetracyclines, which inhibit MMP functions, might represent potential therapeutic approaches to mitigate MMP-related damage during MS.