Neuropathology of the blood-brain barrier and pharmaco-resistance in human epilepsy
Neuropathology of the blood-brain barrier and pharmaco-resistance in human epilepsy
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DOI：
10.1093/brain/aws147
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发表时间：
2012-10-01
期刊：
影响因子：
14.5
通讯作者：
Sisodiya, Sanjay M.
中科院分区：
文献类型：
--
作者：
Liu, Joan Y. W.;Thom, Maria;Sisodiya, Sanjay M.
血脑屏障功能障碍与各种神经系统疾病有关。调节血脑屏障可能具有治疗价值。我们对人类血脑屏障病理生理学的了解有限，这阻碍了进展，部分原因是人体组织的可用性有限，而且人体组织只能提供有关变化时间模式的有限数据。我们通过检查颅内深部电极相关损伤和切除之间间隔不同长度的手术切除脑组织，以及药物敏感或耐药慢性癫痫患者和对照组的死后全脑，解决了这些重要挑战。在这组有价值的资源中，我们发现：（i）在耐药性癫痫患者的致痫海马中存在高度局部化的P-糖蛋白过表达;（ii）这种过表达似乎是P-糖蛋白特异性的，并且不影响其他转运蛋白;（iii）P-糖蛋白在血管内皮和血管胶质细胞的末端足上表达。（形成“双袖”）在耐药癫痫病例中，但在尸检对照或电极相关损伤的手术癫痫组织中没有;（iv）颅内电极记录的急性损伤引起局部炎症，增加的血脑屏障渗透性和对脉管系统的结构变化可检测达至少330天，和（v）慢性癫痫与炎症相关，增强血脑屏障通透性和增加P-糖蛋白表达。癫痫发作的发生似乎是P-糖蛋白过度表达的中心环节。我们的发现具有潜在的临床影响，因为它们直接提高了我们对人类血脑屏障破坏和转运蛋白表达的理解。特别是，我们的研究结果表明，P-糖蛋白在人类中的表达是兼容的一个当前的多药耐药假说的固有假设，和P-糖蛋白表达的特异性上调可能与持续的慢性癫痫发作。在最初的急性损伤后可能有一个治疗窗口，用于预防P-糖蛋白过度表达，因此这是耐药性的一个潜在组成部分。我们的研究结果增加了需要仔细考虑的利益和风险的侵入性脑电图记录耐药癫痫的手术评估。
Blood-brain barrier dysfunction is implicated in various neurological conditions. Modulating the blood-brain barrier may have therapeutic value. Progress is hindered by our limited understanding of the pathophysiology of the blood-brain barrier in humans, partly due to restricted availability of human tissue, and because human tissue can only provide limited data about temporal patterns of change. We addressed these important challenges by examining surgically resected brain tissue with various lengths of interval between intracranial depth electrode-related injury and resection, and post-mortem whole brain from patients with drug-sensitive or drug-resistant chronic epilepsy and controls. In this valuable set of resources, we found that: (i) there is a highly localized overexpression of P-glycoprotein in the epileptogenic hippocampus of patients with drug-resistant epilepsy; (ii) this overexpression appears specific to P-glycoprotein and does not affect other transporters; (iii) P-glycoprotein is expressed on the vascular endothelium and end-feet of vascular glia (forming a 'double cuff') in drug-resistant epileptic cases but not in post-mortem controls or surgical epilepsy tissue with electrode-related injuries; (iv) an acute insult from intracranial electrode recording causes localized inflammation, increased blood-brain barrier permeability and structural changes to vasculature detectable for up to at least 330 days and (v) chronic epilepsy is associated with inflammation, enhanced blood-brain barrier permeability and increased P-glycoprotein expression. The occurrence of seizures appears central to P-glycoprotein overexpression. Our findings have potential clinical impact because they directly improve our understanding of blood-brain barrier disruption and transporter expression in humans. In particular, our findings show that the expression of P-glycoprotein in humans is compatible with the inherent assumptions of one current hypothesis of multidrug resistance, and that the specific upregulation of P-glycoprotein expression is likely to be associated with ongoing chronic seizures. There may be a therapeutic window after initial acute injury for the prevention of P-glycoprotein overexpression, and thus this one potential component of drug resistance. Our findings add to the need for careful consideration of the benefit and risks of invasive electroencephalographic recording in surgical evaluation of drug-resistant epilepsy.