Use of glycosaminoglycans in the treatment of interstitial cystitis: A strategy to improve efficacy

Interstitial cystitis (IC) is a chronic and incurable disease with symptoms including urinary urgency, frequency, nocturia and bladder pain. A recent survey estimated between 130,000 and 170,000 cases of the disease in the United States. The most popular etiological theory on interstitial cystitis is that the glycocalyx of the bladder epithelium is deficient. Accordingly, some of the current treatments are aimed at replacing the missing glycoconjugates by the intravesical administration of heparin, hyaluronic acid, or pentosan polysulfate (PPS) (Elmiron). It is presumed that these anionic polysaccharides act by replacing the missing coat of endogenous glycosaminoglycans (GAGs) on the epithelium. However, biotinylated pentosan polysulfate and heparin showed either no or weak binding to paraffin sections of rabbit and human bladder. The binding of radiolabeled heparin and pentosan sulfate to fresh rabbit bladders was also negligible. In contrast, mucins showed strong staining of the epithelium, indicative of lectin-mediated interactions. In other studies, the binding of biotinylated neoglycoconjugates demonstrated the presence of galactose- and N-acetylglucosamine-binding lectins in bladder epithelium. The presence of galectin-3 and galectin-4 in bladder mucosa was confirmed by molecular biological techniques. Based on these findings, heparin and pentosan polysulfate were modified with galectin-specific saccharide ligands in order to improve their binding to the endogenous lectins in the bladder.