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

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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.

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Acknowledgements

This work was supported by Grant-in-Aid for JSPS Research Fellow (16J11970) and Health and Labor Sciences Research Grant in Japan (17bk01040015h0005).

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Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan

    Yuki Maeda, Keiichi Motoyama, Taishi Higashi, Risako Onodera, Yuki Kurauchi, Hiroshi Katsuki, Yoichi Ishitsuka, Yuki Kondo, Tetsumi Irie & Hidetoshi Arima

  2. Program for Leading Graduate Schools “HIGO (Health Life Science: Interdisciplinary and Glocal Oriented) Program”, Kumamoto University, Kumamoto, Japan

    Yuki Maeda, Tetsumi Irie & Hidetoshi Arima

  3. Center for Animal Resources and Development, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan

    Toru Takeo & Naomi Nakagata

  4. Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan

    Takumi Era

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  1. Yuki Maeda
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10847_2018_835_MOESM1_ESM.pptx

Supplementary Figure S1 TUNEL analysis of brain after intraventricular injection of DM-α-CyD to WT mice. Twenty four h after intraventricular injection of 1 μL of solution containing 431.6 mM DM-α-CyD to WT mice, the brain was collected and 7 μm sequential coronal sections were prepared. TUNEL assay was performed by using the Apoptosis in Situ Detection Kit. The images were representative data of 3 experiments. (PPTX 65 KB)

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Maeda, Y., Motoyama, K., Higashi, T. et al. Lowering effect of dimethyl-α-cyclodextrin on GM1-ganglioside accumulation in GM1-gangliosidosis model cells and in brain of β-galactosidase-knockout mice. J Incl Phenom Macrocycl Chem 93, 53–66 (2019). https://doi.org/10.1007/s10847-018-0835-8

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