Treatment of central nervous system inflammation with inhibitors of basement membrane degradation.
Currently available anti-inflammatory drugs for the treatment of multiple sclerosis (MS) and other inflammatory diseases are generally inadequate, with disease progression not being arrested by the treatments and undesirable side effects posing problems. In response to these deficiencies our laboratories have, over the past 10 years, been developing novel drugs that interfere with the entry of leucocytes into inflammatory sites by inhibiting their passage through the subendothelial basement membrane (BM). This review initially summarizes evidence supporting the hypothesis that the subendothelial BM is a major barrier to the accumulation of leucocytes in inflammatory sites. An important point that has emerged is that breaching of the BM is probably a cooperative process, involving activation- and cytokine-induced degradative enzymes contributed by leucocytes, endothelial cells and platelets. The review then discusses the properties of three separate classes of anti-inflammatory compounds we have developed, namely sulfated polysaccharides/oligosaccharides, phosphosugars, and castanospermine (CS), which inhibit the passage of leukocytes through BM. Each drug type appears to prevent BM degradation by a different mechanism. Sulfated polysaccharides/oligosaccharides mediate their anti-inflammatory effect by inhibiting the endoglycosidase, heparanase, which plays a key role in the solubilization of BM by invading leucocytes. In fact, our studies have highlighted the heparanase enzyme as a major target for future drug development. Phosphosugars probably inhibit inflammation by displacing lysosomal enzymes, which are involved in BM degradation, from cell surface mannose 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 targeting of lysosomal enzymes involved in BM degradation. For reasons which are still unclear, CS specifically inhibits BM degradation by endothelial cells, which results in a characteristic perivascular arrest of leucocytes 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 inflammatory diseases.