Experimental animal model for mucopolysaccharidosis: suramin-induced glycosaminoglycan and sphingolipid accumulation in the rat.

Abstract

ABSTRACGIntracerebral injection of the trypanocidal drug suramin in rats caused the formation of membranous neuronal and neuroglial inclusions. Here we show that intravenous administration of suramin, 500 mg/kg, to 2-month-old rats causes a 5-to 8-fold increase of glycosaminoglycan concentration in the liver within 10 days and a 6-fold increase in urinary glycosaminoglycan excretion. The excess glycosaminoglycans consist of heparan sulfate and dermatan sulfate. Intracerebral injection of 250 Ag of suramin results in a small increase of glycosaminoglycan and larger increase of ganglioside Gm2, GM3, and GD3 concentrations in the treated region of the brain. The activities of the lysosomal enzymes iduronate sulfatase, f-glucuronidase, and hyaluronidase in the liver of the suramintreated mature rats were consistently decreased, whereas those of a-L-iduronidase, heparan N-sulfatase, arylsulfatase B, and others were considerably increased. The activity of iduronate sulfatase was completely inhibited in vitro by suramin at concentrations of 50 pM or hi er. The activity of -glucuronidase was also strongly inhibited by low concentrations of suramin, but this inhibition was partially decreased at higher concentrations of the drug. The inhibition of both enzymes by suramin was noncom titive.-The suramin-treated rat may be a useful experimentaFanimal model of mucopolysaccharidosis.Mucopolysaccharidoses (MPS) are diseases caused by the heritable deficiency of lysosomal enzymes necessary for the degradation of glycosaminoglycans (GAG) (1, 2). The genetic defect results in tissue storage and excessive urinary excretion of various partially degraded GAG. In addition, most of these disorders are characterized by sphingolipid abnormalities, particularly of the brain (3). Recently, one of us found that intracerebral injection of the trypanocidal drug suramin resulted in the formation of membranous neuronal and neuroglial inclusions (4). It was suggested that these inclusion bodies may consist of glycolipids and GAG and that the experiment indicated a possible experimental model for storage diseases. The present study was conducted to examine biochemical alterations in the liver and in the brain of rats after intravenous and intracerebral injection of suramin. The pathologic changes found are similar to those detected in the genetic MPS (5) and suggest that the administration of suramin to rats may provide a useful model for the study of the pathogenesis of these diseases. A preliminary report of this work has been published(6). Table 1. Three groups of confrol rats received 0.5 ml of saline. Multiple intracerebral injections of suramin, totaling 40-250 ,ug in 10 ,l of saline (i.e., 4-25 ,ug/,ul) were given to 10-day-old and to 2-month-old rats. Control rats were given 10 ,l of saline. The rats were sacrificed between 7 and 10 days after injection. The livers were removed, weighed, and frozen in liquid nitrogen. Rats receiving intracerebral injections were sacrificed after 2-5 days. The regions of brain about 4 mm in diameter surr...

Effects of suramin, a polyanionic drug inducing lysosomal storage disorders on tooth germs in vitro

“…In vivo, suramin has been shown to induce a GAG and lipid accumulation in rat tissue [9], including the rat incisor [17]. The present in vitro study also demonstrated an accumulation of GAG and lipids in lysosome-like vacuoles, as shown by the incorporation of radiosulphate and the immunostaining with MC22-33F of phosphatidylcholine and/or sphingomyelin.…”

“…The present in vitro study also demonstrated an accumulation of GAG and lipids in lysosome-like vacuoles, as shown by the incorporation of radiosulphate and the immunostaining with MC22-33F of phosphatidylcholine and/or sphingomyelin. This has been reported for rat tissues after a single administration of the drug [9,10]. The presence of lipid inclusions in the maturing presecretory ameloblasts is likely due to the inhibition by suramin of enzymes involved in lipid degradation.…”

Phospholipids in Amelogenesis and Dentinogenesis

“…Suramin, a polysulfonated naphtylurea with polyanionic character, used as an anti-trypanosomal drug, is taken into cells by endocytosis, accumulates in lysosomes, and inhibits phagosome-lysosome fusion (Hart and Young, 1975). Following intravenous administration, suramin induces an accumulation of GAGs and sphingolipids (Constantopoulos et al, 1980) due to inhibition of many lysosomal enzymes. The function of various ion pumps is inhibited (Moriyama and Nelson, 1988).…”

Changes in the Catalytic Activities of Proteoglycan-Degrading Lysosomal Enzymes in Parenchymal and Non-Parenchymal Liver Cells and in Serum During the Development of Experimental Liver Fibrosis

“…The reduced catalytic activity of this endoglycosidase might be responsible for the accumulation of the respective types of glycosaminoglycans, in particular of chondroitin sulphate, dermatan sulphate and hyaluronate (4,8) possible Inhibition of the degradation of glycosaminoglycans due to a decrease of endoglycosidically active hyaluronate-4-glycanohydfolase; the former enzymes act mainly on oligosaccharides (34,35), and in the case of chondroitin sulphate and dermätan sulphate they act on the desulphated oligosaccharides at the non-reducing terminal (36). The important role of hyaluronate-4-glycanohydrolase in the catabolism of liver glycosaminoglycans is suggested by Constantopoulos et al (37) from studies with the trypanocidal drug suramin. In the presence of this drug the strong Inhibition of the enzyme is accompanied by an increase in the total glycosaminoglycan concentration in rat liver tissue.…”