Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult
Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult
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DOI：
10.1111/j.1750-3639.2003.tb00485.x
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发表时间：
2003-10-01
期刊：
影响因子：
6.4
通讯作者：
Schaeren-Wiemers, N
中科院分区：
文献类型：
--
作者：
Graumann, U;Reynolds, R;Schaeren-Wiemers, N
多发性硬化是一种中枢神经系统慢性炎症性疾病，导致髓鞘的局灶性破坏，导致病变形成的最早变化仍然未知。我们研究了12个正常出现的白色物质样品的基因表达模式，从10个死后MS脑。微阵列分析揭示了参与维持细胞内稳态的基因上调，以及已知在缺血预处理后诱导的神经保护机制。这一点最好地通过转录因子（例如HIF-1 alpha）和相关PI 3 K/Akt信号通路的上调以及其靶基因（例如VEGF受体1）的上调来说明。此外，一般的神经保护反应对氧化应激的建议。这些分子变化可能反映了细胞对MS慢性进行性病理生理学的适应。或者，它们也可能表明神经保护机制的激活，允许保留CNS的细胞和功能特性。我们的数据引入了MS分子发病机制的新概念，其中缺血预处理是神经保护的主要机制。对潜在机制的进一步了解可能会导致开发新的更具体的治疗方法来保护常驻细胞，从而最大限度地减少进行性少突胶质细胞和轴突损失。
Multiple sclerosis is a chronic inflammatory disease of the CNS leading to focal destruction of myelin, still the earliest changes that lead to lesion formation are not known. We have studied the gene-expression pattern of 12 samples of normal appearing white matter from 10 post-mortem MS brains. Microarray analysis revealed upregulation of genes involved in maintenance of cellular homeostasis, and in neural protective mechanisms known to be induced upon ischemic preconditioning. This is best illustrated by the upregulation of the transcription factors such as HIF-1alpha and associated PI3K/Akt signalling pathways, as well as the upregulation of their target genes such as VEGF receptor 1. In addition, a general neuroprotective reaction against oxidative stress is suggested. These molecular changes might reflect an adaptation of cells to the chronic progressive pathophysiology of MS. Alternatively, they might also indicate the activation of neural protective mechanisms allowing preservation of cellular and functional properties of the CNS. Our data introduce novel concepts of the molecular pathogenesis of MS with ischemic preconditioning as a major mechanism for neuroprotection. An increased understanding of the underlying mechanisms may lead to the development of new more specific treatment to protect resident cells and thus minimize progressive oligondendrocyte and axonal loss.