Study of the molecular mechanism of synaptogenesis using withanolides, novel anti-dementia drugs

新型抗痴呆药物茄内酯突触发生的分子机制研究

• 批准号: 17500249
• 负责人: TOHDA Chihiro
• 金额: $ 2.46万
• 依托单位: University of Toyama
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17500249/
• 关键词: Withanoside IV; Sominone; Memory improvement; Dendrite; RET; ACK1; Neuronal network; Spinal cord injury; withanolide類; シナプス形成; 末梢性ミエリン; axon; neuregulin-I; estrogen receptor; PI3 kinase; 抗痴呆; 中枢神経損傷; neuron; myelin

Oral administration of withanoside IV (10 μmol/kg/day), an isolated compound from roots of Withania somnifera significantly improved memory deficits in Aβ(25-35)-injected (25 nmol, i.c.v.) mice and prevented loss of axons, dendrites, and synapses. The treatment with withanoside IV could enhance the object recognition memory in normal mice. In spinal cord injured mice, per oral treatment with withanoside IV (10 μmol/kg/day, for 21 days) improved locomotor functions in mice, and increased axonal density and the peripheral nervous system myelin level.Sominone, an aglycone of withanoside IV, was identified as the main metabolite after oral administration of withanoside IV. Sominone (1 μM) induced axonal and dendritic regeneration and synaptic reconstruction significantly in cultured rat cortical neurons damaged by 10 μM Aβ(25-35).To clarify the molecular mechanism of sominone, we identified receptors or associated molecules in primary cultured neurons, which were phosphorylated by sominone stimulation using phosphorylation antibody arrays. The level of phosphorylated RET increased in microglias and neurons. The level of phosphorylated ACK1 increased in neurons. Knockdown experiments using siRNA showed that both RET and ACK1 were involved in dedritic extension. These results suggest that roles of RET and ACK1 as key molecules for reconstruction of the neuronal

口服睡茄苷 IV（10 μmol/kg/天）（一种从睡茄根中分离出来的化合物）可显着改善 Aβ(25-35) 注射（25 nmol，静脉注射）小鼠的记忆缺陷，并防止轴突、树突、口服醉茄苷 IV 可以增强正常小鼠的物体识别记忆。 （10 μmol/kg/天，持续21天）改善小鼠的运动功能，增加轴突密度和周围神经系统髓磷脂水平。Sominone是茄苷IV的苷元，被确定为口服茄苷IV后的主要代谢产物Sominone (1 μM) 在 10 μM 损伤的培养大鼠皮层神经元中显着诱导轴突和树突再生以及突触重建Aβ(25-35)。为了阐明索米农的分子机制，我们鉴定了原代培养的神经元中的受体或相关分子，这些受体或相关分子通过使用磷酸化抗体阵列的索米农刺激而磷酸化。磷酸化的小胶质细胞和神经元中的磷酸化RET水平增加。使用 siRNA 的敲低实验表明 RET 和 ACK1 都参与了树突延伸。这些结果表明 RET 和 ACK1 的作用。 ACK1作为神经元重建的关键分子

项目成果

ADHD関連疾患治療剤

ADHD相关疾病治疗剂

• 发表时间: 2008

Characterization of anti-neurodegenerative effects of Polygala tenuifolia in Aβ(23-35)-treated cortical neurons.

细叶远志对 Aβ(23-35) 处理的皮质神经元的抗神经退行性作用的表征。

• 发表时间: 2006
• 期刊: Biol.Pharm.Bull. 29
• 作者: Naito R.;Tohda C.
• 通讯作者: Tohda C.

Synaptic reconstruction effect of natural medicines; identifying new anti-dementia drugs and analyzing the molecular mechanism of synaptogenesis

天然药物的突触重建作用；

• 发表时间: 2005
• 作者: Tohda;C
• 通讯作者: C

Scientific basis for the anti-dementia drugs of constituents from Ashwagandha(Withania somnifera).

Ashwagandha（Withania somnifera）成分抗痴呆药物的科学依据。

• 发表时间: 2005
• 期刊: 和漢医薬学雑誌 22
• 作者: Tohda C.;Komatsu K. and Kuboyama T.
• 通讯作者: Komatsu K. and Kuboyama T.

Metabolite 1 of protopanaxadiol-type saponins, an axonal regenerative factor, stimulates teneurin-2 followed by PI3-kinase cascade.

原人参二醇型皂苷的代谢物 1（一种轴突再生因子）刺激 teneurin-2，随后刺激 PI3 激酶级联反应。

• 发表时间: 2005
• 作者: 中西類子;東田千尋;橋本斎;小松かつ子;横澤隆子
• 通讯作者: 横澤隆子