Inhibition of p53 transcriptional activity: A potential target for future development of therapeutic strategies for primary demyelination
Inhibition of p53 transcriptional activity: A potential target for future development of therapeutic strategies for primary demyelination
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DOI：
10.1523/jneurosci.0184-08.2008
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发表时间：
2008-06-11
影响因子：
5.3
通讯作者：
Casaccia-Bonnefil, Patrizia
中科院分区：
文献类型：
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作者：
Li, Jiadong;Ghiani, Cristina A.;Casaccia-Bonnefil, Patrizia
在多发性硬化患者的脑中检测到少突胶质细胞病、小胶质细胞浸润和髓鞘再生缺乏，并伴有高水平的转录因子p53。在这项研究中，我们使用的脱髓鞘，少突胶质细胞病变和小胶质细胞浸润的特点，cuprizone模型，以确定p53抑制的效果。与未处理的对照组相比，在缺乏p53或接受p53抑制剂pifithrin-alpha全身给药的小鼠中观察到髓鞘保存、小胶质细胞募集减少和基因表达。在体外，在p53（-/-）原代小胶质细胞培养物或pifithrin-alpha处理的小胶质细胞BV 2细胞中也观察到脂多糖诱导的基因表达水平降低。在室管膜下区的Sox 2+多能祖细胞中观察到缺乏或抑制p53的额外有益作用，其响应于增加的增殖和少突胶质细胞生成。基于这些结果，我们提出暂时抑制p53作为主要以少突胶质细胞病为特征的脱髓鞘疾病的潜在治疗靶点。
Oligodendrogliopathy, microglial infiltration, and lack of remyelination are detected in the brains of patients with multiple sclerosis and are accompanied by high levels of the transcription factor p53. In this study, we used the cuprizone model of demyelination, characterized by oligodendrogliopathy and microglial infiltration, to define the effect of p53 inhibition. Myelin preservation, decreased microglial recruitment, and gene expression were observed in mice lacking p53 or receiving systemic administration of the p53 inhibitor pifithrin-alpha, compared with untreated controls. Decreased levels of lypopolysaccharide- induced gene expression were also observed in vitro, in p53(-/-) primary microglial cultures or in pifithrin-alpha- treated microglial BV2 cells. An additional beneficial effect of lack or inhibition of p53 was observed in Sox2+ multipotential progenitors of the subventricular zone that responded with increased proliferation and oligodendrogliogenesis. Based on these results, we propose transient inhibition of p53 as a potential therapeutic target for demyelinating conditions primarily characterized by oligodendrogliopathy.