The effect of STAT3 inhibition on status epilepticus and subsequent spontaneous seizures in the pilocarpine model of acquired epilepsy.
The effect of STAT3 inhibition on status epilepticus and subsequent spontaneous seizures in the pilocarpine model of acquired epilepsy.
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DOI：
10.1016/j.nbd.2013.09.003
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发表时间：
2014-02
影响因子：
6.1
通讯作者：
Brooks-Kayal AR
中科院分区：
文献类型：
--
作者：
Grabenstatter HL;Del Angel YC;Carlsen J;Wempe MF;White AM;Cogswell M;Russek SJ;Brooks-Kayal AR
毛果芸香碱诱导的癫痫持续状态（SE）会导致啮齿动物颞叶癫痫（TLE），并激活JAK/STAT通路。在当前研究中，我们评估在SE发作后早期短暂暴露于JAK/STAT通路的选择性抑制剂（WP1066）是否会影响SE的严重程度，或者通过抑制STAT3调控的基因转录来降低后期自发性癫痫发作频率。在SE发作时接受全身性WP1066或赋形剂的大鼠在SE期间以及一个月内持续进行视频脑电图监测，以评估随时间推移的癫痫发作频率。在癫痫发生阶段，对接受WP1066和赋形剂治疗的大鼠评估pSTAT3以及STAT3调控基因（包括：ICER、Gabra1、c - myc、mcl - 1、细胞周期蛋白D1和bcl - xl）的蛋白质和/或mRNA水平，以确定给予WP1066对SE和慢性癫痫的急性影响。在SE发作后的第一个小时内给予WP1066（两个50mg/kg剂量）会导致pSTAT3的短暂抑制以及自发性癫痫发作频率的长期降低。WP1066改变慢性癫痫的严重程度，但不影响SE或细胞死亡。早期给予WP1066会在SE后24小时降低STAT3转录的已知下游靶点，包括细胞周期蛋白D1和mcl - 1的水平，它们分别在细胞周期进程和细胞存活中起作用。这些发现揭示了脑损伤后JAK/STAT通路的一种潜在影响，这种影响在生理上很重要，并且可能提供一个新的治疗靶点，可用于预防癫痫的发生和/或进展。
Pilocarpine-induced status epilepticus (SE), which results in temporal lobe epilepsy (TLE) in rodents, activates the JAK/STAT pathway. In the current study, we evaluate whether brief exposure to a selective inhibitor of the JAK/STAT pathway (WP1066) early after the onset of SE effects the severity of SE or reduces later spontaneous seizure frequency via inhibition of STAT3-regulated gene transcription. Rats that received systemic WP1066 or vehicle at the onset of SE were continuously video-EEG monitored during SE and for one month to assess seizure frequency over time. Protein and/or mRNA levels for pSTAT3, and STAT3-regulated genes including: ICER, Gabra1, c-myc, mcl-1, cyclin D1, and bcl-xl were evaluated in WP1066 and vehicle-treated rats during stages of epileptogenesis to determine the acute effects of WP1066 administration on SE and chronic epilepsy. WP1066 (two 50 mg/kg doses) administered within the first hour after onset of SE results in transient inhibition of pSTAT3 and long-term reduction in spontaneous seizure frequency WP1066 alters the severity of chronic epilepsy without affecting SE or cell death. Early WP1066 administration reduces known downstream targets of STAT3 transcription 24 hours after SE including cyclin D1 and mcl-1 levels, known for their roles in cell-cycle progression and cell survival, respectively. These findings uncover a potential effect of the JAK/STAT pathway after brain injury that is physiologically important and may provide a new therapeutic target that can be harnessed for the prevention of epilepsy development and/or progression.
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