L-PDMP improves glucosylceramide synthesis and behavior in rats with focal ischemia
L-PDMP improves glucosylceramide synthesis and behavior in rats with focal ischemia
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DOI：
10.1179/016164108x339396
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发表时间：
2008-11-01
影响因子：
1.9
通讯作者：
Masuda, Hiroyuki
中科院分区：
文献类型：
--
作者：
Hisaki, Harumi;Okazaki, Tomoki;Masuda, Hiroyuki
背景：研究表明外源性给药鞘糖脂（GSLs）可诱导培养神经细胞的神经突生长。此外，葡萄糖神经酰胺合成酶的激活剂l- threo-1-phenyl-2- decanoylaminos -3- morpholinos -1-propanol （LPDMP）被认为在同一培养体系中对GSL的生物合成和神经营养作用都有刺激作用。为了研究GSLs对体内局灶性脑缺血的影响，我们在大脑左中动脉永久性闭塞后的慢性期向大鼠腹腔注射L-PDMP，观察GSLs的水平及其对行为改变的影响。采用高效薄层色谱法分离脑苷、鞘磷脂（SM）和神经酰胺（GLC），内标分别为n -庚烷醇- d -脑苷、n -庚烷醇- d -鞘磷脂和n -庚烷醇- d -鞘磷脂，测定缺血皮质中脑苷、鞘磷脂（SM）和神经酰胺的含量。为了确定脑苷的糖组分，直接用GLC分析了其甲基糖苷经甲醇分解后的三甲基硅基化衍生物。结果：L-PDMP处理可使神经节苷的前体糖基神经酰胺增加2.4倍，但对缺血大脑皮层SM和神经酰胺的水平无明显影响。经L-PDMP处理的缺血大鼠在Morris水迷宫任务中表现出记忆和学习的再习得改善。结论：L-PDMP具有促进糖基神经酰胺生物合成和改善神经功能的药理作用。[神经医学杂志]2008；30: 979 - 984)
Background: It has been shown that exogenic administration of glycosphingolipids (GSLs) induces outgrowth of neurites from cultured nerve cells. Furthermore, the activator of glucosylceramide synthase, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (LPDMP), is thought to exhibit stimulatory effects on both the biosynthesis and neurotrophic actions of GSL in the same culture system. To investigate the effect of GSLs on focal cerebral ischemia in vivo, L-PDMP was injected into the intraperitoneal space of rats during the chronic phase following permanent occlusion of the left middle cerebral artery (MCA) and thereafter, the levels of GSLs and their effects on behavioral changes were examinedMethods: The levels of cerebrosides, sphingomyelin (SM) and ceramide in the ischemic cortex were measured by gas -liquid chromatography (GLC) after separation by high-performance thinlayer chromatography, using the internal standards N-heptadecanoyl-D-cerebroside, N-heptadecanoyl-D- sphingomyelin and N-heptadecanoyl-D-sphingosine, respectively. To determine the sugar components of the cerebrosides, the trimethylsilylated derivatives of their methylglycosides after methanolysis were analysed directly by GLC.Results: The L-PDMP treatment induced a 2.4-fold increase in glucosylceramide, the precursor of gangliosides, but no changes were evident in the levels of SM and ceramide in the ischemic cerebral cortex. The ischemic rats treated with L-PDMP showed improved re-acquisition of memory and learning in the Morris water maze task.Conclusion: These results suggest that the pharmacological effects of L-PDMP include significant facilitation of glucosylceramide biosynthesis and improvement of neural function. [Neurol Res 2008; 30: 979-984]