Rigau Valérie, Morin Mélanie, Rousset Marie-Claude, de Bock Frédéric, Lebrun Aurore, Coubes Philippe, Picot Marie-Christine, Baldy-Moulinier Michel, Bockaert Joël, Crespel Arielle, Lerner-Natoli Mireille
Centre National de la Recherche Scientifique UMR5203, Université Montpellier 1, Université Montpellier 2, F34094 Montpellier, France.
Brain. 2007 Jul;130(Pt 7):1942-56. doi: 10.1093/brain/awm118. Epub 2007 May 28.
Previous studies from our group, focusing on neuro-glial remodelling in human temporal lobe epilepsy (TLE), have shown the presence of immature vascular cells in various areas of the hippocampus. Here, we investigated angiogenic processes in hippocampi surgically removed from adult patients suffering from chronic intractable TLE, with various aetiologies. We compared hippocampi from TLE patients to hippocampi obtained after surgery or autopsy from non-epileptic patients (NE). We quantified the vascular density, checked for the expression of angiogenic factors and their receptors and looked for any blood-brain barrier (BBB) leakage. We used a relevant model of rat limbic epilepsy, induced by lithium-pilocarpine treatment, to understand the sequence of events. In humans, the vessel density was significantly higher in TLE than in NE patients. This was neither dependent on the aetiology nor on the degree of neuronal loss, but was positively correlated with seizure frequency. In the whole hippocampus, we observed many complex, tortuous microvessels. In the dentate gyrus, when the granular layer was dispersed, long microvessels appeared radially orientated. Vascular endothelial factor (VEGF) and tyrosine kinase receptors were detected in different types of cells. An impairment of the BBB was demonstrated by the loss of tight junctions and by Immunoglobulines G (IgG) leakage and accumulation in neurons. In the rat model of TLE, VEGF over-expression and BBB impairment occurred early after status epilepticus, followed by a progressive increase in vascularization. In humans and rodents, angiogenic processes and BBB disruption were still obvious in the chronic focus, probably activated by recurrent seizures. We suggest that the persistent leakage of serum IgG in the interstitial space and their uptake by neurons may participate in hypoperfusion and in neuronal dysfunction occurring in TLE.
我们团队之前专注于人类颞叶癫痫（TLE）中神经胶质重塑的研究表明，海马体的各个区域存在未成熟的血管细胞。在此，我们研究了从患有各种病因的慢性顽固性TLE成年患者手术切除的海马体中的血管生成过程。我们将TLE患者的海马体与非癫痫患者（NE）手术后或尸检后获得的海马体进行了比较。我们量化了血管密度，检查了血管生成因子及其受体的表达，并寻找任何血脑屏障（BBB）渗漏情况。我们使用锂-匹鲁卡品治疗诱导的大鼠边缘性癫痫相关模型来了解事件序列。在人类中，TLE患者的血管密度显著高于NE患者。这既不依赖于病因，也不依赖于神经元丢失的程度，而是与癫痫发作频率呈正相关。在整个海马体中，我们观察到许多复杂、曲折的微血管。在齿状回中，当颗粒层分散时，长微血管呈放射状排列。在不同类型的细胞中检测到血管内皮生长因子（VEGF）和酪氨酸激酶受体。紧密连接的丧失以及免疫球蛋白G（IgG）在神经元中的渗漏和积累证明了血脑屏障的损伤。在TLE大鼠模型中，癫痫持续状态后早期出现VEGF过表达和血脑屏障损伤，随后血管化逐渐增加。在人类和啮齿动物中，慢性病灶中血管生成过程和血脑屏障破坏仍然明显，可能由反复发作的癫痫激活。我们认为，血清IgG在间质空间的持续渗漏及其被神经元摄取可能参与了TLE中发生的灌注不足和神经元功能障碍。
