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

Abstract

Summary Currently available anti-in¯ammatory drugs for the treatment of multiple sclerosis (MS) and other in¯ammatory diseases are generally inadequate, with disease progression not being arrested by the treatments and undesirable side e ects posing problems. In response to these de®ciencies our laboratories have, over the past 10 years, been developing novel drugs that interfere with the entry of leucocytes into in¯ammatory 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 in¯ammatory 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 antiin¯ammatory compounds we have developed, namely sulfated polysaccharides/oligosaccharides, phosphosugars, and castanospermine (CS), which inhibit the passage of leucocytes through BM. Each drug type appears to prevent BM degradation by a di erent mechanism. Sulfated polysaccharides/oligosaccharides mediate their antiin¯ammatory e ect 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 in¯ammation 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 speci®cally inhibits BM degradation by endothelial cells, which results in a characteristic perivascular arrest of leucocytes in in¯ammatory sites. Overall, our studies have established that inhibitors of subendothelial BM degradation represent viable anti-in¯ammatory agents. It is hoped that future work will result in the development of a totally new class of highly e ective, subtle and non-toxic anti-in¯ammatory drugs for the treatment of MS and other in¯ammatory diseases.

Heparanase upregulation by colonic epithelium in inflammatory bowel disease

“…Among the few cell types that express heparanase under normal physiological conditions are placental cytothrophoblasts, skin keratinocytes and blood borne cells such as lymphocytes, neutrophils, macrophages and platelets. 2,3 Heparanase was localized to tertiary granules of neutrophils 6,27 and mast cells, 28 and its release by degranulation has been implicated in diapedesis of a number of immune cells, including neutrophils, macrophages, mast cells, dendritic cells and lymphocytes, 13,29,30 thus strongly implying heparanase as a pro-inflammatory mediator. Surprisingly, however, only a weak heparanase staining was observed in immune cells of IBD specimens ( Figure 2).…”

Heparanase Induces Endothelial Cell Migration via Protein Kinase B/Akt Activation

“…Heparanase was localized to tertiary granules of neutrophils (12,13) and mast cells (7) and was released upon tumor necrosis factor-␣ and calcium ionophore treatments, respectively. Heparanase release by degranulation has been implicated in diapedesis and extravasation of a number of immune cells, including neutrophils, macrophages, and lymphocytes (8,14,15), while heparanase inhibitors exhibited an anti-inflammatory activity (15). Cleavage of HS side chains by degranulated heparanase during inflammation may facilitate the passage of blood-borne normal and malignant cells into tissues by altering the composition and structural integrity of the subendothelial ECM (1,8,14).…”

Heparanase Uptake Is Mediated by Cell Membrane Heparan Sulfate Proteoglycans

“…Under normal conditions, heparanase activity is restricted to the placenta and skin tissues and to blood-borne cells such as platelets, neutrophils, monocytes, mast cells, and T lymphocytes (1,4,5,(7)(8)(9)(10)(11)(12). In these cells, heparanase is thought to be stored in specific granules, and its release by degranulation has been implicated in diapedesis and extravasation of a number of immune cells (4,5,(11)(12)(13). Heparanase up-regulation has been documented in a variety of human tumors correlating, in some cases, with increased vascular density and poor postoperative survival (14 -17).…”