Blood-brain barrier breakdown-inducing astrocytic transformation: novel targets for the prevention of epilepsy.
Blood-brain barrier breakdown-inducing astrocytic transformation: novel targets for the prevention of epilepsy.
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DOI：
10.1016/j.eplepsyres.2009.03.005
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发表时间：
2009-08
影响因子：
2.2
通讯作者：
Heinemann, Uwe
中科院分区：
文献类型：
--
作者：
Friedman, Alon;Kaufer, Daniela;Heinemann, Uwe
癫痫发生是常见的脑损伤，如创伤，缺血和感染。然而，损伤相关癫痫发生的机制仍然未知。最近的研究表明，血脑屏障（BBB）的完整性受损，在癫痫发生。在这里，我们回顾积累的实验证据支持原发性血脑屏障病变在癫痫发生的潜在参与。来自动物实验的数据表明，BBB倾向性动物的原发性破裂发展为局灶性新皮质癫痫，随后是神经元损失和功能受损。发现白蛋白从循环中外渗到脑神经元中足以诱导癫痫发生。白蛋白与星形胶质细胞中的转化生长因子β受体2（TGFβR2）结合，并诱导快速转录修饰、星形胶质细胞转化和功能障碍。我们强调了一个新的级联事件，这是由BBB通透性增加，最终导致神经元功能障碍，癫痫和细胞损失。我们回顾了星形胶质细胞和TGFβ通路在癫痫发生中的重要作用的潜在机制和现有的实验证据。最后，我们回顾了来自人类临床数据的证据，支持BBB病变参与癫痫。我们认为，原发性血管损伤，特别是血脑屏障的破坏和修复，是神经血管单位内相互作用改变的关键因素，因此可以作为新的治疗靶点。
Epileptogenesis is common following brain insults such as trauma, ischemia and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Recent studies demonstrated impaired integrity of the blood–brain barrier (BBB) during epileptogenesis. Here we review accumulating experimental evidence supporting the potential involvement of primary BBB lesion in epileptogenesis. Data from animal experiments demonstrate that primary breakdown of the BBB prone animals to develop focal neocortical epilepsy that is followed by neuronal loss and impaired functions. The extravasation of albumin from the circulation into the brain neuropil was found to be sufficient for the induction of epileptogenesis. Albumin binds to transforming growth factor β receptor 2 (TGFβR2) in astrocytes and induces rapid transcriptional modifications, astrocytic transformation and dysfunction. We highlight a novel cascade of events which is initiated by increased BBB permeability, eventually leading to neuronal dysfunction, epilepsy and cell loss. We review potential mechanisms and existing experimental evidence for the important role of astrocytes and the TGFβ pathway in epileptogenesis. Finally, we review evidence from human clinical data supporting the involvement of BBB lesion in epilepsy. We propose that primary vascular injury, and specifically BBB breakdown and repair, are key elements in altered interactions within the neurovascular unit and thus may serve as new therapeutic targets.
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影响因子：
5.3
作者：
Djukic, Biljana;Casper, Kristen B.;McCarthy, Ken D.
通讯作者：
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通讯作者：
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