Treatment of central nervous system inflammation with inhibitors of basement membrane degradation

Immunology and Cell Biology
Christopher R ParishD O Willenborg

Abstract

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...Continue Reading

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