Iminosugar-Based Inhibitors of Glucosylceramide Synthase Increase Brain Glycosphingolipids and Survival in a Mouse Model of Sandhoff Disease
Iminosugar-Based Inhibitors of Glucosylceramide Synthase Increase Brain Glycosphingolipids and Survival in a Mouse Model of Sandhoff Disease
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DOI：
10.1371/journal.pone.0021758
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发表时间：
2011-06-29
期刊：
影响因子：
3.7
通讯作者：
Marshall, John
中科院分区：
文献类型：
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作者：
Ashe, Karen M.;Bangari, Dinesh;Marshall, John
神经性鞘糖脂病是溶酶体贮积症的一个亚组，目前尚无有效的治疗方法。一种潜在的方法是使用葡糖神经酰胺合酶（GCS）抑制剂的底物减少疗法，以减少在溶酶体中积累的葡糖神经酰胺和相关鞘糖脂的合成。Genz-529468是一种血脑屏障渗透性亚氨基糖基GCS抑制剂，用于在Sandhoff病小鼠模型中评价这一概念，该模型在内脏器官和CNS中蓄积鞘糖脂GM 2。正如预期的那样，口服该药物可以抑制肝脏GM 2的积累。奇怪的是，在大脑中，治疗导致GM 2水平轻微增加，葡萄糖神经酰胺水平增加20倍。脑葡萄糖神经酰胺水平的增加可能是由于非溶酶体葡萄糖神经酰胺酶Gba 2的同时抑制。用另一种基于亚胺糖的GCS抑制剂NB-DNJ观察到类似的结果。尽管CNS中的鞘糖脂出现了这些意外增加，但治疗仍然延迟了运动功能和协调性的丧失，并延长了Sandhoff小鼠的寿命。这些结果表明，在Sandhoff小鼠中观察到的CNS获益可能不一定是由于底物减少治疗，而是由于脱靶效应。
The neuropathic glycosphingolipidoses are a subgroup of lysosomal storage disorders for which there are no effective therapies. A potential approach is substrate reduction therapy using inhibitors of glucosylceramide synthase (GCS) to decrease the synthesis of glucosylceramide and related glycosphingolipids that accumulate in the lysosomes. Genz-529468, a blood-brain barrier-permeant iminosugar-based GCS inhibitor, was used to evaluate this concept in a mouse model of Sandhoff disease, which accumulates the glycosphingolipid GM2 in the visceral organs and CNS. As expected, oral administration of the drug inhibited hepatic GM2 accumulation. Paradoxically, in the brain, treatment resulted in a slight increase in GM2 levels and a 20-fold increase in glucosylceramide levels. The increase in brain glucosylceramide levels might be due to concurrent inhibition of the non-lysosomal glucosylceramidase, Gba2. Similar results were observed with NB-DNJ, another iminosugar-based GCS inhibitor. Despite these unanticipated increases in glycosphingolipids in the CNS, treatment nevertheless delayed the loss of motor function and coordination and extended the lifespan of the Sandhoff mice. These results suggest that the CNS benefits observed in the Sandhoff mice might not necessarily be due to substrate reduction therapy but rather to off-target effects.