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Roles of Glial Cells for Neurodegeneration in Prion Diseases

胶质细胞在朊病毒病神经变性中的作用

基本信息

批准号：
15380202
负责人：
NAKAMURA Yoichi
金额：
$ 8.32万
依托单位：
Osaka Prefecture University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

It is unknown how affects Amphotericin B (AmB), reported to be a therapeutic drug against prion diseases, on microglial function. Cultured microglia prepared from rat new-born brain were stimulated to produce nitric oxide (NO) by prion peptide (106-126) (PrP), and also by AmB. The level of the NO production stimulated by AmB was enhanced by the presence of the PrP. These results suggest a certain interaction between AmB and PrP and the interaction modulates the microglial cell function. The elucidation of this interaction might be a key for the therapeutic mechanism of AmB against prion diseases.The physiological functions of prion protein is speculative; however, it is suggested that prion protein is involves in the, mechanism of Cu transport, which is an essential metal for superoxide dismutase (SOD), through cell membrane. We have established the method for the measurement of extracellular SOD (EC-SOD) activity in the living cells. The activities of EC-SOD of cultured astrocytes from rat embryo's brain decreased to a half after stimulation by lipopolysaccharide (LPS) for 24 hr, whereas the intracellular SODs (cytoplasmic and mitochondrial) increased. On the other hand, the activity of SOD in the culture medium increased by LPS dose-dependently. These results suggest that EC-SOD is released from cell surface into the medium. Astrocytes may play an important role for the regulation of brain parenchymal level of active oxygen species by changing localization of EC-SOD ; protecting surrounding neurons from oxidative stress.

两性霉素B（AmB）是一种治疗朊病毒疾病的药物，目前尚不清楚它对小胶质细胞功能的影响。用朊病毒肽（106-126）（PrP）和AmB刺激培养的新生大鼠脑小胶质细胞产生一氧化氮（NO）。PrP的存在增强了AmB刺激的NO产生水平。这些结果表明AmB和PrP之间存在一定的相互作用，并且这种相互作用调节小胶质细胞的功能。阐明这种相互作用可能是AmB治疗朊病毒疾病机制的关键。朊病毒蛋白的生理功能尚不清楚;但有人认为朊病毒蛋白参与了超氧化物歧化酶（SOD）必需金属铜通过细胞膜的转运机制。建立了活细胞胞外SOD（EC-SOD）活性测定方法。培养的大鼠胚胎脑星形胶质细胞经脂多糖（LPS）刺激24小时后，EC-SOD活性下降一半，而细胞内SOD（胞浆和线粒体SOD）活性增加。另一方面，培养液中的SOD活性增加LPS的剂量依赖性。这些结果表明，EC-SOD从细胞表面释放到培养基中。星形胶质细胞可能通过改变EC-SOD的定位，调节脑实质活性氧水平，保护周围神经元免受氧化应激损伤。