Luan Zhuo, Li Linjing, Higaki Katsumi, Nanba Eiji, Suzuki Yoshiyuki, Ohno Kousaku
Division of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Japan.
Brain Dev. 2013 Apr;35(4):317-22. doi: 10.1016/j.braindev.2012.05.008. Epub 2012 Jun 7.
Gaucher disease (GD), caused by a defect of acid β-glucosidase (β-Glu), is one of the most common sphingolipidoses. Recently, ambroxol, an FDA-approved drug used to treat airway mucus hypersecretion and hyaline membrane disease in newborns, was identified as a chemical chaperone for GD. In the present study, we investigated the chaperone activity and toxicity of ambroxol on both cultured GD patient cells and normal mice. We found that ambroxol treatment significantly increased N370S, F213I, N188S/G193W and R120W mutant β-Glu activities in GD fibroblasts with low cytotoxicity. Additionally, we measured the β-Glu activity in the tissues of normal mice which received water containing increasing concentrations of ambroxol ad libitum for one week. No serious adverse effect was observed during this experiment. Ambroxol significantly increased the β-Glu activity in the spleen, heart and cerebellum of the mice. This result showed its oral availability and wide distribution and chaperone activity in the tissues, including the brain, and its lack of acute toxicity. These characteristics of ambroxol would make it a potential therapeutic chaperone in the treatment of GD with neurological manifestations.
戈谢病（GD）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之一。最近，氨溴索，一种经美国食品药品监督管理局（FDA）批准用于治疗新生儿气道黏液分泌过多和透明膜病的药物，被确定为GD的化学伴侣分子。在本研究中，我们研究了氨溴索对培养的GD患者细胞和正常小鼠的伴侣活性及毒性。我们发现，氨溴索处理显著提高了GD成纤维细胞中N370S、F213I、N188S/G193W和R120W突变型β-Glu的活性，且细胞毒性较低。此外，我们测量了正常小鼠组织中的β-Glu活性，这些小鼠自由饮用含浓度递增的氨溴索的水一周。在此实验过程中未观察到严重不良反应。氨溴索显著提高了小鼠脾脏、心脏和小脑的β-Glu活性。该结果表明其口服可用性、在包括脑在内的组织中的广泛分布和伴侣活性，以及其缺乏急性毒性。氨溴索的这些特性使其成为治疗有神经表现的GD的潜在治疗性伴侣分子。
