L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol stimulates ganglioside biosynthesis, neurite outgrowth and synapse formation in cultured cortical neurons, and ameliorates memory deficits in ischemic rats.
L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol stimulates ganglioside biosynthesis, neurite outgrowth and synapse formation in cultured cortical neurons, and ameliorates memory deficits in ischemic rats.
复制标题
L-threo-1-苯基-2-decanoylamino-3-morpholino-1-propanol 刺激培养的皮质神经元中的神经节苷脂生物合成、神经突生长和突触形成，并改善缺血大鼠的记忆缺陷。
DOI：
10.18388/abp.1998_4241
复制
发表时间：
1998
影响因子：
1.7
通讯作者：
M. Fujiwara
中科院分区：
文献类型：
--
作者：
J. Inokuchi;Y. Kuroda;S. Kosaka;M. Fujiwara
为了解决脑神经节苷脂在突触可塑性中的作用，使用合成神经酰胺类似物 1-苯基-2-癸酰氨基-3-吗啉代-1-丙醇 (PDMP) 来操纵培养的皮质神经元中神经节苷脂的生物合成。神经元之间细胞内 Ca2+ 的自发同步振荡活动（代表突触形成）通过 D-threo-PDMP（一种葡萄糖神经酰胺合酶抑制剂）消耗内源性神经节苷脂而受到抑制。功能性突触形成的减少通过补充 GQ1b 而不是通过其他神经节苷脂而正常化，这表明神经节苷脂 GQ1b 的从头合成对于突触活性至关重要（Mizutani A. 等人，Biochem. Biophys. Res. Commun. 222, 494-498, 1996）。另一方面，抑制剂的对映体 L-threo-PDMP 可以提高包括神经节苷脂在内的鞘糖脂的细胞水平。本文介绍了我们关于 L-threo-PDMP 体外和体内神经营养作用的最新发现。我们发现 L-PDMP 可以通过激活 GM3、GD3 和 GQ1b 合酶来上调神经突生长、功能性突触形成和神经节苷脂生物合成。同时，L-PDMP 也促进了 p42 丝裂原激活蛋白激酶的活性。为了评估该药物对长期记忆的功效，使用8臂径向迷宫任务训练大鼠2周，然后通过4血管闭塞诱导前脑缺血（10分钟×2次，间隔60分钟）。缺血后 24 小时开始重复 L-threo-PDMP 治疗（40 mg/kg，腹膜内注射 6 天，每天两次），改善了良好学习的空间记忆的缺陷，证明了神经酰胺类似物在治疗神经退行性疾病方面的潜在治疗用途。
To address the role of brain gangliosides in synaptic plasticity, the synthetic ceramide analog, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) was used to manipulate the biosynthesis of gangliosides in cultured cortical neurons. Spontaneous synchronized oscillatory activity of intracellular Ca2+ between the neurons, which represents synapse formation, was suppressed by the depletion of endogenous gangliosides by D-threo-PDMP, an inhibitor of glucosylceramide synthase. The decreased functional synapse formation was normalized by supplementation of GQ1b but not by the other gangliosides, suggesting that de novo synthesis of ganglioside GQ1b is essential for the synaptic activity (Mizutani A. et al., Biochem. Biophys. Res. Commun. 222, 494-498, 1996). On the other hand, the enantiomer of the inhibitor, L-threo-PDMP, could elevate cellular levels of glycosphingolipids including gangliosides. This paper presents our recent findings on the neurotrophic actions of L-threo-PDMP in vitro and in vivo. We found that L-PDMP could up-regulate neurite outgrowth, functional synapse formation and ganglioside biosynthesis through activating GM3, GD3 and GQ1b synthases. Simultaneously, the activity of p42 mitogen-activated protein kinase was also facilitated by L-PDMP. To evaluate the efficacy of this drug on long term memory, rats were trained for 2 weeks using an 8-arm radial maze task, and then forebrain ischemia was induced by 4-vessel occlusion (for 10 min x 2 with a 60 min interval). Repeated treatment of L-threo-PDMP (40 mg/kg, i.p. for 6 days, twice a day) starting 24 h after the ischemia, improved the deficit of the well-learned spatial memory, demonstrating the potential therapeutic use of the ceramide analog for treatment of neurodegenerative disorders.
DOI：
--
发表时间：
1993
期刊：
Advances in lipid research
影响因子：
--
作者：
N. Radin;J. A. Shayman;J. Inokuchi
通讯作者：
N. Radin;J. A. Shayman;J. Inokuchi
DOI：
10.1073/pnas.89.12.5670
发表时间：
1992-06-15
影响因子：
11.1
作者：
MURTHY, VN;FETZ, EE
通讯作者：
FETZ, EE
影响因子：
56.9
作者：
BADING, H;GREENBERG, ME
通讯作者：
GREENBERG, ME