Levetiracetam treatment influences blood-brain barrier failure associated with angiogenesis and inflammatory responses in the acute phase of epileptogenesis in post-status epilepticus mice
Levetiracetam treatment influences blood-brain barrier failure associated with angiogenesis and inflammatory responses in the acute phase of epileptogenesis in post-status epilepticus mice
复制标题
DOI：
10.1016/j.brainres.2016.09.038
复制
发表时间：
2016-12-01
期刊：
影响因子：
2.9
通讯作者：
Kataoka, Yasufumi
中科院分区：
文献类型：
--
作者：
Itoh, Kouichi;Ishihara, Yasuhiro;Kataoka, Yasufumi
我们之前的研究表明，在地西泮终止癫痫持续状态（SE）后使用左乙拉西坦（LEV）治疗可能通过抑制脑水肿事件引起的神经毒性来预防自发性复发性癫痫发作的发生。在本研究中，我们确定了在SE终止后LEV治疗可能的分子和细胞机制。为了评估LEV对SE后脑改变的影响，我们重点研究了与血管生成和脑炎症相关的血脑屏障（BBB）功能障碍。连续使用LEV可抑制SE后2天海马血脑屏障渗漏暂时性增加。在同一时间点，LEV处理显著抑制了cd31阳性内皮未成熟细胞数量的增加和血管生成因子的表达。这些发现表明，se诱导的血脑屏障衰竭导致新生血管的增加导致血脑屏障通透性增加，而LEV治疗可以预防这些脑改变。此外，在潜伏期的急性期，海马小胶质细胞和星形胶质细胞中致痫靶点的促炎反应被激活，这些促炎相关分子的上调被LEV治疗抑制。这些发现表明，在癫痫发作后急性期，LEV可能通过抗血管生成和抗血脑屏障功能障碍参与神经保护。
Our previous study showed that treatment with levetiracetam (LEV) after status epilepticus (SE) termination by diazepam might prevent the development of spontaneous recurrent seizures via the inhibition of neurotoxicity induced by brain edema events. In the present study, we determined the possible molecular and cellular mechanisms of LEV treatment after termination of SE. To assess the effect of LEV against the brain alterations after SE, we focused on blood-brain barrier (BBB) dysfunction associated with angiogenesis and brain inflammation. The consecutive treatment of LEV inhibited the temporarily increased BBB leakage in the hippocampus two days after SE. At the same time point, the LEV treatment significantly inhibited the increase in the number of CD31-positive endothelial immature cells and in the expression of angiogenic factors. These findings suggested that the increase in neovascularization led to an increase in BBB permeability by SE-induced BBB failure, and these brain alterations were prevented by LEV treatment. Furthermore, in the acute phase of the latent period, pro-inflammatory responses for epileptogenic targets in microglia and astrocytes of the hippocampus activated, and these upregulations of pro-inflammatory-related molecules were inhibited by LEV treatment. These findings suggest that LEV is likely involved in neuroprotection via anti-angiogenesis and antiinflammatory activities against BBB dysfunction in the acute phase of epileptogenesis after SE.