Cyclodextrin alleviates neuronal storage of cholesterol in Niemann-Pick C disease without evidence of detectable blood-brain barrier permeability.
Cyclodextrin alleviates neuronal storage of cholesterol in Niemann-Pick C disease without evidence of detectable blood-brain barrier permeability.
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DOI：
10.1007/s10545-012-9583-x
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发表时间：
2013-05
影响因子：
4.2
通讯作者：
Begley, David J.
中科院分区：
文献类型：
--
作者：
Pontikis, Charles C.;Davidson, Cristin D.;Walkley, Steven U.;Platt, Frances M.;Begley, David J.
Niemann Pick C型病是一种遗传性常染色体隐性遗传病，其特征是内体/溶酶体腔室内未酯化胆固醇和鞘脂的积累。据观察，羟丙基-β-环糊精（HPBCD）的管理延迟了临床症状的发作，减少了神经元细胞内胆固醇和神经节苷脂的积累。据推测，HPBCD通过容易进入中枢神经系统并直接与神经元和其他脑细胞相互作用来发挥其作用，以促进从内体/溶酶体晚期腔室中去除储存的胆固醇。在这里，我们提出了反驳这一假设的证据。我们使用了两种成熟的技术来精确测量大脑对血液中溶质的吸收，并表明HPBCD没有明显的交叉进入大脑。两种技术分别是脑原位灌注和腹腔注射，然后进行多时间点回归分析。两项研究均未证明成年或新生小鼠对HPBCD的摄取具有显著的时间依赖性。然而，HPBCD的可分布体积（0.113±0.010ml/g）超过了脑血浆和血管体积的可接受值。事实上，它几乎是蔗糖的三倍（0.039±0.006 ml/g）。我们认为，这表明HPBCD与脑血管内皮细胞表面结合，并可能提供一种动员和清除中枢神经系统胆固醇的机制。
Niemann Pick type C disease is an inherited autosomal recessive disorder characterised by the accumulation of unesterified cholesterol and sphingolipids within the endosomal/lysosomal compartments. It has been observed that the administration of hydroxypropyl-β-cyclodextrin (HPBCD) delays onset of clinical symptoms and reduces accumulation of cholesterol and gangliosides within neuronal cells. It was assumed that HPBCD exerts its action by readily entering the CNS and directly interacting with neurones and other brain cells to facilitate removal of stored cholesterol from the late endosomal/lysosomal compartment. Here, we present evidence that refutes this hypothesis. We use two well established techniques for accurately measuring brain uptake of solutes from blood and show that there is no significant crossing of HPBCD into the brain. The two techniques are brain in situ perfusion and intraperitoneal injection followed by multi-time-point regression analysis. Neither study demonstrates significant, time-dependent uptake of HPBCD in either adult or neonatal mice. However, the volume of distribution available to HPBCD (0.113±0.010ml/g) exceeds the accepted values for plasma and vascular volume of the brain. In fact, it is nearly three times larger than that for sucrose (0.039±0.006 ml/g). We propose that this indicates cell surface binding of HPBCD to the endothelium of the cerebral vasculature and may provide a mechanism for the mobilization and clearance of cholesterol from the CNS.
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DOI：
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发表时间：
2004-12-01
影响因子：
3.5
作者：
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发表时间：
2010-03-23
影响因子：
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作者：
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影响因子：
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