Progress toward acetate supplementation therapy for Canavan disease:: Glyceryl triacetate administration increases acetate, but not N-acetylaspartate, levels in brain
Progress toward acetate supplementation therapy for Canavan disease:: Glyceryl triacetate administration increases acetate, but not N-acetylaspartate, levels in brain
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DOI：
10.1124/jpet.105.087536
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发表时间：
2005-10-01
影响因子：
3.5
通讯作者：
Namboodiri, MAA
中科院分区：
文献类型：
--
作者：
Mathew, R;Arun, P;Namboodiri, MAA
Canavan病（CD）是一种致命的遗传性神经退行性疾病，由天冬氨酸酰化酶基因突变引起，天冬氨酸酰化酶是一种将n -乙酰天冬氨酸（NAA）水解成l -天冬氨酸和乙酸的酶。由于天冬氨酸酰化酶定位于少突胶质细胞，而naa衍生的醋酸盐被纳入髓磷脂脂中，我们假设少突胶质细胞中的醋酸盐缺乏是导致CD病理的原因，我们建议补充醋酸盐作为一种可能的治疗方法。为了实现这一目标，我们研究了口服三醋酸甘油（GTA）和醋酸钙增加小鼠大脑中醋酸水平的有效性。同时测定大鼠灌胃GTA后脑内乙酸酯和NAA的浓度。我们发现脑内醋酸酯水平呈剂量和时间依赖性增加，在20至21日龄的小鼠中，以5.8 g/kg GTA的剂量在1至2小时内观察到17倍的增加。在这些条件下，大脑中的NAA水平没有显著增加。对处于不同发育阶段的小鼠进行的研究表明，维持大脑中类似的醋酸盐水平所需的GTA剂量随着年龄的增长而增加。此外，GTA作为醋酸来源的效果明显优于醋酸钙。长期给药至25日龄的GTA在小鼠中没有导致任何明显的病理。基于这些结果和目前食品和药物管理局批准的GTA作为食品添加剂的使用，我们提出它是一个潜在的候选物，用于醋酸补充治疗CD。
Canavan disease (CD) is a fatal genetic neurodegenerative disorder caused by mutations in the gene for aspartoacylase, an enzyme that hydrolyzes N-acetylaspartate (NAA) into L-aspartate and acetate. Because aspartoacylase is localized in oligodendrocytes, and NAA-derived acetate is incorporated into myelin lipids, we hypothesize that an acetate deficiency in oligodendrocytes is responsible for the pathology in CD, and we propose acetate supplementation as a possible therapy. In our preclinical efforts toward this goal, we studied the effectiveness of orally administered glyceryl triacetate (GTA) and calcium acetate for increasing acetate levels in the murine brain. The concentrations of brain acetate and NAA were determined simultaneously after intragastric administration of GTA. We found that the acetate levels in brain were increased in a dose- and time-dependent manner, with a 17-fold increase observed at 1 to 2 h in 20- to 21-day-old mice at a dose of 5.8 g/kg GTA. NAA levels in the brain were not significantly increased under these conditions. Studies using mice at varying stages of development showed that the dose of GTA required to maintain similarly elevated acetate levels in the brain increased with age. Also, GTA was significantly more effective as an acetate source than calcium acetate. Chronic administration of GTA up to 25 days of age did not result in any overt pathology in the mice. Based on these results and the current Food and Drug Administration-approved use of GTA as a food additive, we propose that it is a potential candidate for use in acetate supplementation therapy for CD.