TREATMENT OF CENTRAL-NERVOUS-SYSTEM INFLAMMATION WITH INHIBITORS OF BASEMENT-MEMBRANE DEGRADATION

Currently available anti-inflammatory drugs for the treatment of multi ple sclerosis (MS) and other inflammatory diseases are generally inade quate, with disease progression not being arrested by the treatments a nd undesirable side effects posing problems. In response to these defi ciencies our laboratories have, over the past 10 years, been developin g novel drugs that interfere with the entry of leucocytes into inflamm atory sites by inhibiting their passage through the subendothelial bas ement membrane (BM). This review initially summarizes evidence support ing the hypothesis that the subendothelial BM is a major barrier to th e accumulation of leucocytes in inflammatory sites. An important point that has emerged is that breaching of the BM is probably a cooperativ e process, involving activation-and cytokine-induced degradative enzym es contributed by leucocytes, endothelial cells and platelets. The rev iew then discusses the properties of three separate classes of antiinf lammatory compounds we have developed, namely sulfated polysaccharides /oligosaccharides, phosphosugars, and castanospermine (CS), which inhi bit the passage of leucocytes through BM. Each drug type appears to pr event BM degradation by a different mechanism. Sulfated polysaccharide s/oligosaccharides mediate their antiinflammatory effect by inhibiting the endoglycosidase, heparanase, which plays a key role in the solubi lization of BM by invading leucocytes. In fact, our studies have highl ighted the heparanase enzyme as a major target for future drug develop ment. Phosphosugars probably inhibit inflammation by displacing lysoso mal enzymes, which are involved in BM degradation, from cell surface m annose 6-phosphate receptors. This mechanism of expressing degradative enzymes on the cell surface is particularly evident with activated T lymphocytes. On the other hand, CS interferes with appropriate targeti ng of lysosomal enzymes involved in BM degradation. For reasons which are still unclear, CS specifically inhibits BM degradation by endothel ial cells, which results in a characteristic perivascular arrest of le ucocytes in inflammatory sites. Overall, our studies have established that inhibitors of subendothelial BM degradation represent viable anti -inflammatory agents. It is hoped that future work will result in the development of a totally new class of highly effective, subtle and non -toxic anti-inflammatory drugs for the treatment of MS and other infla mmatory diseases.