Morphological and functional changes due to drug-induced lysosomal storageof sulphated glycosaminoglycans in the rat retina

A series of dicationic amphiphilic drugs, most of them immunomodulatory age nts, are known to induce generalised lysosomal storage of sulphated glycosa minoglycans (GAGs) in rats and in cultured cells of several species includi ng man. The present study deals with the cytological effects of two experim ental immunomodulatory acridine derivatives upon the retina of rats. The an imals were treated orally with compound CL-90.100 (3,6-bis[2-(diethylamino) ethoxy]acridine) or an analogue for periods up to 22 weeks at a dose range of 60-90 mg/kg, body weight and the retinae examined by light and electron microcopy. ERG measurements were done initially and after 16 weeks of treat ment. All types of retinal cells developed abnormal cytoplasmic vacuoles wh ich represented the ultrastructural counterpart of lysosomal GAG storage as demonstrated by histochemical and cytochemical staining experiments. The r etinal pigment epithelium and the Muller cells were most prominently affect ed, photoreceptor cells to a lesser degree, and retinal neurons to varying degrees. The topographical distribution of the drug as detected by fluoresc ence microscopy closely resembled the distribution of the GAG accumulation in the retinal layers. After treatment for 16 weeks, the a-and b-wave ampli tudes in the ERG were significantly reduced compared with the controls. Con clusion: the glycosaminoglycan storage in pigment epithelium is reminiscent of that seen in some inherited mucopolysaccharidoses of humans. When a giv en cell type shows lysosomal accumulation of glycosaminoglycans as a conseq uence of impaired degradation, it can be assumed to be engaged in the turno ver of glycosaminoglycans under normal conditions. Thus the present results suggest that not only the retinal pigment epithelium but also Muller cells , photoreceptor cells, and, to variable degree, retinal neurons are normall y involved in the catabolism of sulphated glycosaminoglycans. We believe th at the lysosomal storage of glycosaminoglycans caused secondary cellular di sturbance responsible for the functional chances shown by electroretinograp hy.