Luan Zhuo, Ninomiya Haruaki, Ohno Kousaku, Ogawa Seiichiro, Kubo Takatoshi, Iida Masami, Suzuki Yoshiyuki
Division of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Japan.
Brain Dev. 2010 Nov;32(10):805-9. doi: 10.1016/j.braindev.2009.12.005. Epub 2010 Jan 13.
Gaucher disease (GD), mainly caused by a defect of acid β-glucosidase (β-Glu), is the most common sphingolipidosis. We have previously shown that a carbohydrate mimic N-octyl-β-valienamine (NOV), an inhibitor of β-Glu, could increase the protein level and enzyme activity of various mutant β-Glu in cultured GD fibroblasts, suggesting that NOV acted as a pharmacological chaperone to accelerate transport and maturation of this mutant enzymes. In the present study, the NOV effect was evaluated for β-Glu activity, tissue distribution and adverse effects in normal mice. We measured the β-Glu activity in tissues of normal mice which received water containing increasing concentrations of NOV ad libitum for 1 week. Fluid intake and body weight were measured periodically throughout the study. Measurement of tissue NOV concentration, blood chemistry and urinalysis were performed at the end of the study. The results showed that NOV had no impact on the body weight but fluid intake in the 10mM NOV group mice decreased and there was a moderate increase in blood urea nitrogen (BUN). No other adverse effect was observed during this experiment. Tissue NOV concentration increased in all tissues examined with increasing NOV doses. No inhibitory effect of NOV on β-Glu was observed. Furthermore, NOV increased the β-Glu activity in the liver, spleen, muscle and cerebellum of the mice significantly. This study on NOV showed its oral availability and wide tissue distribution, including the brain and its lack of acute toxicity. These characteristics of NOV would make it a potential therapeutic chaperone in the treatment of GD with neurological manifestations and selected mutations.
戈谢病（GD）主要由酸性β-葡萄糖苷酶（β-Glu）缺陷引起，是最常见的鞘脂贮积症。我们之前已经表明，一种碳水化合物模拟物N-辛基-β-缬氨酰胺（NOV），作为β-Glu的抑制剂，能够增加培养的戈谢病成纤维细胞中各种突变型β-Glu的蛋白水平和酶活性，这表明NOV作为一种药理伴侣加速了这种突变酶的转运和成熟。在本研究中，评估了NOV对正常小鼠β-Glu活性、组织分布及不良反应的影响。我们测量了自由饮用含不同浓度NOV水溶液1周的正常小鼠组织中的β-Glu活性。在整个研究过程中定期测量液体摄入量和体重。在研究结束时进行组织中NOV浓度的测定、血液生化分析和尿液分析。结果显示，NOV对体重没有影响，但10mM NOV组小鼠的液体摄入量减少，血尿素氮（BUN）有适度升高。在该实验中未观察到其他不良反应。随着NOV剂量增加，所有检测组织中的NOV浓度均升高。未观察到NOV对β-Glu有抑制作用。此外，NOV显著增加了小鼠肝脏、脾脏、肌肉和小脑中的β-Glu活性。这项关于NOV的研究表明其口服可用性、广泛的组织分布，包括脑内，且无急性毒性。NOV的这些特性使其成为治疗有神经表现和特定突变的戈谢病的潜在治疗伴侣。
