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Elucidation of endogenous protective factors regulating neuronal death in neurodegenerative disorders.

阐明调节神经退行性疾病中神经元死亡的内源性保护因子。

基本信息

批准号：
12470524
负责人：
AKAIKE Akinori
金额：
$ 7.74万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470524/
关键词：
nitric oxide glutamate neuronal death neuroprotective factor fetal calf serum slice of substantia nigra estradiol vitamin D ステロイド線条体条件培地胎仔血性パーキンソン病

项目摘要

This study was aimed to elucidate the protective action of endogenous factors regulating neuronal death induced by glutamate and reactive oxygen species (ROS). We carried out three protects by using in vitro primary cultures.1) We elucidated the chemical structure of non-protein neuroprotective substance isolated from the ether extract of fetal calf serum. NMR analysis revealed the structure of the compound being hydroxy- 17-methylsufinylatisan-19-oic acid. This compound was a novel atisane-type diterpenoid. The compound was named "serofendic acid" as it was isolated from serum and possessed potent neuroprotective activity.2) The role neuronal activity in the survival of dopaminergic neurons was investigated by using slice cultures of the rat mesencephalon. The study with glutamate receptor antagonists suggested that calcium influx induced by depolarization under moderate and persistent stimulation of glutamate receptors accelerates neuronal survival and that CAMP plays an important role in the neurotrophic effect of glutamate receptor-mediated calcium influx.3) We examined the neuroprotective effects of endogenous substances including vitamin D, estradiol and neurotrophins. Those substances inhibited glutamate neurotoxicity in a concentration dependent manner. They also inhibited neurotoxicity induced by calcium ionophore and ROS. Intracellular ROS generation was also prevented by the pretreatment of those substances. These results suggest that vitamin D, estradiol and neurotrophins elicit protective actions against glutamate neurotoxicity to promote neuronal survival by reducing radical stress during the process of neurodegenerative disorders.

本研究旨在阐明内源性因子对谷氨酸和活性氧（ROS）诱导的神经元死亡的保护作用。利用体外原代培养进行了3次保护。1)阐明了从胎牛血清醚提取物中分离得到的非蛋白神经保护物质的化学结构。核磁共振分析表明该化合物的结构为羟基- 17-甲基亚甲酰基atisan-19-oic酸。该化合物是一种新的atisane型二萜类化合物。该化合物被命名为“血清芬地酸”，因为它是从血清中分离出来的，具有强大的神经保护活性。2)采用大鼠中脑切片培养，探讨神经元活性在多巴胺能神经元存活中的作用。对谷氨酸受体拮抗剂的研究表明，在适度和持续刺激谷氨酸受体的情况下，去极化诱导的钙内流加速了神经元的存活，CAMP在谷氨酸受体介导的钙内流的神经营养作用中起重要作用。3)考察了维生素D、雌二醇、神经营养因子等内源性物质的神经保护作用。这些物质以浓度依赖的方式抑制谷氨酸的神经毒性。它们还能抑制钙离子载体和活性氧引起的神经毒性。这些物质的预处理也可以阻止细胞内ROS的产生。这些结果表明，在神经退行性疾病过程中，维生素D、雌二醇和神经营养因子可通过减少自由基应激，引起对谷氨酸神经毒性的保护作用，从而促进神经元存活。