Interstitial cystitis is poorly understood, and the causes and pathophysiology for IC are still unknown. Many theories have been proposed about the etiology of IC, but none has been definitively proven. There are no cures for IC and clinicians use a variety of empiric treatments, based on the proposed causes for IC. However, none of these treatments are consistently effective, and some patients remain unable to find any relief. One popular theory about IC is that the glycocalyx of the bladder epithelium is deficient. Accordingly, some of the current treatments are aimed at replacing the missing glycoconjugates by intravesical or oral administration of sulfated polysaccharides, such as heparin and pentosan polysulfate (Elmiron). It is unknown why these treatments show improvement of symptoms in only some IC patients, and why the response is usually slow. One possible reason is that the highly anionic and readily water-soluble sulfated polysaccharides do not adhere to the bladder well enough to exert their beneficial effect. An exploratory study is proposed for the development of an innovative approach that should not only increase the efficiency of sulfated polysaccharides for patients who respond, but may also benefit some patients who do not currently respond. The plan is to improve the binding and thereby strengthen and prolong the adherence of intravesically administered drugs to the bladder. The experimental strategy is to modify the sulfated polysaccharides with specific saccharide ligands, so that they will bind to endogenous lectins in the bladder. In order to choose the saccharide structures for this purpose it is first necessary to identify the lectins present in the bladder epithelium of rabbit (an animal model for initial binding studies) and human. Preliminary studies have demonstrated the presence of galactose- and N-acetylglucosamine-binding lectins in both rabbit and human bladders. Further detailed investigations are needed to complete the biochemical characterization of the major bladder lectins and specifically, elucidate their saccharide specificities. Once identified, the saccharide ligands will be conjugated to sulfated polysaccharides and the binding of the conjugates to bladder will be evaluated. Although the initial studies will be on sulfated polysaccharide treatments of IC, the same strategy could also be applied to improve treatment of various other bladder diseases. For example, prolonged binding of antibiotics to the urothelium may help to treat or prevent urinary tract infections.
| Beyder, A; Gibbons, S J; Mazzone, A et al. (2016) Expression and function of the Scn5a-encoded voltage-gated sodium channel NaV 1.5 in the rat jejunum. Neurogastroenterol Motil 28:64-73 |
| Neshatian, Leila; Strege, Peter R; Rhee, Poong-Lyul et al. (2015) Ranolazine inhibits voltage-gated mechanosensitive sodium channels in human colon circular smooth muscle cells. Am J Physiol Gastrointest Liver Physiol 309:G506-12 |
| Muthusamy, Arivalagan; Erickson, Deborah R; Sheykhnazari, Mostafa et al. (2006) Enhanced binding of modified pentosan polysulfate and heparin to bladder--a strategy for improved treatment of interstitial cystitis. Urology 67:209-13 |
| Erickson, Deborah R; Sheykhnazari, Mostafa; Bhavanandan, Veer P (2006) Molecular size affects urine excretion of pentosan polysulfate. J Urol 175:1143-7 |
| Bhavanandan, V P; Puch, S; Guo, X et al. (2001) Galectins and other endogenous carbohydrate-binding proteins of animal bladder. Adv Exp Med Biol 491:95-108 |
