以炎症为靶点治疗慢性缺血后的脑白质损伤

发布时间：2018-07-06 19:51

本文选题：慢性缺血 + 白质损伤　；参考：《中国药理学与毒理学杂志》2016年10期

【摘要】：大脑长期慢性缺血将可能导致脑白质损伤及认知功能损害,造成皮质下缺血性血管性痴呆。目前临床上缺乏针对性的有效药物,因此急需针对其发病机制寻找减轻髓鞘丢失或促进髓鞘再生修复的治疗新靶点。课题组研究发现,慢性缺血后髓鞘再生过程受到抑制,主要是因为脑室下区增殖的前体细胞OPC向白质区迁移过程受到阻碍,因而OPC迁移障碍是慢性缺血后髓鞘再生和白质修复的关键限速步骤。进一步发现,慢性缺血早期胶质细胞高表达炎症因子IL-1β,其受体拮抗剂(IL-1Ra)或基因敲除其受体(IL-1R1 KO)可以促进脑室下区的OPC(逆转录病毒标记)向脑白质区迁移的过程,但对OPC的增殖没有影响;而在IL-1R1 KO小鼠上,通过腺病毒介导的IL-1R1过表达可以逆转OPC迁移的增多。并且发现阻断IL-1β受体IL-1R1后可以促进髓鞘再生、神经传导功能恢复及改善认知功能。该工作提示控制炎症反应、促进OPC的迁移可能是减轻慢性缺血引起的白质损伤的重要途径,而IL-1β及其受体IL-1R1是重要的药物干预靶点。同时IL-1β的多肽类似物Kd PT可以在慢性缺血后进入脑内促进OPC的迁移,从而促进白质修复和改善认知功能。此外,小胶质细胞抑制剂米诺环素在慢性缺血早期应用可显著减轻白质损伤和认知功能损害,其机制主要是通过减少成熟少突胶质细胞凋亡、促进脑室下区OPC的增殖从而促进髓鞘再生过程,为二次开发"老药"米诺环素提供了重要的实验依据。以上研究通过针对胶质细胞介导的炎症反应,发现多个促进慢性缺血后白质修复的新靶点,为皮层下缺血性血管性痴呆治疗提供了新途径。
[Abstract]:Chronic cerebral ischemia may lead to white matter damage and cognitive impairment and subcortical ischemic vascular dementia. At present, there is a lack of effective drugs in clinic, so it is urgent to find a new target to reduce the myelin loss or promote the regeneration of myelin sheath. The study group found that the process of myelin regeneration was inhibited after chronic ischemia, mainly because the migration of OPC, a proliferating precursor cell in the subventricular area, to the white matter area was blocked. Therefore, OPC migration disorder is a critical limiting step for myelin regeneration and white matter repair after chronic ischemia. It was further found that the overexpression of IL-1 尾, a receptor antagonist (IL-1Ra) or gene knockout receptor (IL-1R1KO) in glial cells at the early stage of chronic ischemia, could promote the migration of OPC (retrovirus labeled) from the subventricular region to the white matter area, In IL-1R1KO mice, the overexpression of IL-1R1 mediated by adenovirus could reverse the increase of OPC migration. It was also found that blocking IL-1 尾 receptor IL-1R1 could promote myelin regeneration, restore nerve conduction function and improve cognitive function. This work suggests that controlling inflammation and promoting the migration of OPC may be an important way to reduce the white matter injury induced by chronic ischemia, and IL-1 尾 and its receptor IL-1R1 are important targets of drug intervention. At the same time, KdPT, a peptide analogues of IL-1 尾, could promote the migration of OPC into the brain after chronic ischemia, thus promoting white matter repair and improving cognitive function. In addition, the application of minocycline, a microglial inhibitor, in the early stage of chronic ischemia can significantly reduce white matter damage and cognitive impairment, mainly by reducing apoptosis of mature oligodendrocytes. It can promote the proliferation of OPC in the subventricular region and promote the regeneration of myelin sheath, which provides an important experimental basis for the secondary development of minocycline. Through the glial cell-mediated inflammatory response, the above studies have found several new targets to promote the white matter repair after chronic ischemia, which provides a new approach for the treatment of subcortical ischemic vascular dementia.
【作者单位】：浙江大学药医药学部理系神经科学研究中心;
【基金】：国家自然科学基金(81273490,81273506,81473186,81221003) 中央高校基本科研业务费项目(2016FZA7014)
【分类号】：R749.13

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