Lowering effect of dimethyl-α-cyclodextrin on GM1-ganglioside accumulation in GM1-gangliosidosis model cells and in brain of β-galactosidase-knockout mice

Abstract

GM1-gangliosidosis (GM1G) is caused by a deficiency of β-galactosidase, resulting in the excessive accumulation of GM1-ganglioside (GM1) in lysosomes of cells, particularly in the nerve cells (neurons). There is no treatment available for patients with GM1G. Meanwhile, cyclodextrins (CyDs) are cyclic oligosaccharides, which are widely used in the pharmaceutical field. We previously reported that 2, 6-di-O-methyl-α-CyD (DM-α-CyD) extracted phospholipids from lipid rafts, which are abundant with sphingolipids including GM1. Therefore, in the present study, we investigated the effects of α-CyDs on GM1 levels in GM1G model cells and in brain of GM1G model mice. The interaction of DM-α-CyD with GM1 was stronger than that of 2-hydroxypropyl-α-CyD. Additionally, DM-α-CyD significantly reduced GM1 levels in GM1G model cells at 1 mM for 24 h. Furthermore, DM-α-CyD decreased GM1 levels in brain after an intraventricular administration to GM1G model mice without any significant side effects. These results strongly suggest that DM-α-CyD decreased the accumulation of GM1 in not only GM1G model cells but also GM1G model mice. Collectively, DM-α-CyD may have the potential as a therapeutic drug for GM1G.