N-butyldeoxygalactonojirimycin reduces brain ganglioside and GM2 content in neonatal Sandhoff disease mice

被引：34

作者：

Baek, Rena C. ^{[1
]}

Kasperzyk, Julie L. ^{[1
]}

Platt, Frances A. ^{[2
]}

Seyfried, Thomas N. ^{[1
]}

机构：

[1] Boston Coll, Dept Biol, Chestnut Hill, MA 02467 USA

[2] Univ Oxford, Dept Pharmacol, Oxford, England

来源：

NEUROCHEMISTRY INTERNATIONAL | 2008年 / 52卷 / 06期

关键词：

beta-hexosaminidase; gangliosidosis; glycosphingolipids; GM2; neurodegenerative disease; substrate reduction therapy (SRT);

D O I：

10.1016/j.neuint.2007.12.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Sandhoff disease involves the CNS accumulation of ganglioside GM2 and asialo-GM2 (GA2) due to inherited defects in the beta-subunit gene of beta-hexosammidase A and B (Hexb gene). Accumulation of these glycosphingolipids (GSLs) produces progressive neurodegeneration, ultimately leading to death. Substrate reduction therapy (SRT) aims to decrease the rate of glycosphingolipid (GSL) biosynthesis to compensate for the impaired rate of catabolism. The imino sugar, N-butyldeoxygalactonojirimycin (NB-DGJ) inhibits the first committed step in GSL biosynthesis. NB-DGJ treatment, administered from postnatal day 2 (p-2) to p-5 (600 mg/kg/day)), significantly reduced total brain ganglioside and GM2 content in the Sandhoff disease (Hexb(-/-)) mice, but did not reduce the content of GA2. We also found that NB-DGJ treatment caused a slight, but significant elevation in brain sialidase activity. The drug had no adverse effects on viability, body weight, brain weight, or brain water content in the mice. No significant alterations in neutral lipids or acidic phospholipids were observed in the NB-DGJ-treated Hexb(-/-) mice. Our results show that NB-DGJ is effective in reducing total brain ganglioside and GM2 content at early neonatal ages. (C) 2007 Elsevier Ltd. All rights reserved.

引用

页码：1125 / 1133

页数：9

共 74 条

[1] Improved outcome of N-butyldeoxygalactonojirimycin-mediated substrate reduction therapy in a mouse model of Sandhoff disease [J].