腹侧海马连合的电刺激可延迟实验性癫痫发作，并与 microRNA 表达改变有关。
Electrical stimulation of the ventral hippocampal commissure delays experimental epilepsy and is associated with altered microRNA expression.
机构信息
Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, University Hospital Frankfurt and Center for Personalized Translational Epilepsy Research (CePTER), Goethe University, Frankfurt, Germany; Department of Neurology, Philipps University, Marburg, Germany.
Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, University Hospital Frankfurt and Center for Personalized Translational Epilepsy Research (CePTER), Goethe University, Frankfurt, Germany; Department of Neurology, Philipps University, Marburg, Germany.
出版信息
Brain Stimul. 2019 Nov-Dec;12(6):1390-1401. doi: 10.1016/j.brs.2019.06.009. Epub 2019 Jun 7.
BACKGROUND
Up to 80% of mesial temporal lobe epilepsy patients with hippocampal sclerosis (mTLE-HS) are resistant to pharmacological treatment, often necessitating surgical resection. Deep brain stimulation (DBS) has emerged as an alternative treatment for patients who do not qualify for resective brain surgery. Brain stimulation may also exert disease-modifying effects, and noncoding microRNAs have recently been proposed to shape the gene expression landscape in epilepsy.
OBJECTIVE
We compared the effect of DBS of 4 different hippocampal target regions on epileptogenesis and manifest epilepsy in a rat model of mTLE-HS. To explore mechanisms, we profiled the effect of the most effective DBS paradigm on hippocampal microRNA levels.
METHODS
MTLE-HS was induced by electrical stimulation of the perforant pathway (PP) in rats. This paradigm leads to spontaneous seizures within 4 weeks. We investigated DBS of 4 targets: PP, fimbria fornix (FF) formation, dentate gyrus (DG) and ventral hippocampal commissure (VHC). We applied both high- (130 Hz) and low-frequency (5 Hz or 1 Hz) stimulation. Functional microRNAs were identified in the hippocampus immediately after VHC-DBS and after a 97-day recording period by sequencing small RNAs bound to Argonaute-2, a component of the miRNA silencing complex.
RESULTS
Low frequency DBS of the VHC significantly delayed the occurrence of the first spontaneous recurrent seizure in the PPS model by ∼300%, from 19 to 56 days. No other stimulation regime altered the latency phase. Upregulation of 5 microRNAs during epileptogenesis was suppressed by VHC-stimulation.
CONCLUSION
We conclude that DBS of the VHC delays epilepsy in the PPS model in rats and is associated with differential regulation of several miRNAs. Additional studies are required to determine whether VHC-regulated miRNAs serve causal roles in the anti-epileptogenic effects of this DBS model.
背景
高达 80%的伴有海马硬化（mTLE-HS）的内侧颞叶癫痫患者对药物治疗有抗药性，通常需要进行手术切除。深部脑刺激（DBS）已成为不符合手术切除标准的患者的替代治疗方法。脑刺激还可能产生疾病修饰作用，最近提出非编码 microRNAs 可以塑造癫痫中的基因表达图谱。
目的
我们比较了 DBS 刺激 4 个不同海马目标区域对 mTLE-HS 大鼠模型中癫痫发生和表现性癫痫的影响。为了探索机制，我们分析了最有效的 DBS 范式对海马 microRNA 水平的影响。
方法
通过电刺激穿通通路（PP）在大鼠中诱导 mTLE-HS。该范式在 4 周内导致自发性癫痫发作。我们研究了 4 个目标的 DBS：PP、穹窿伞（FF）形成、齿状回（DG）和腹侧海马连合（VHC）。我们应用了高频（130 Hz）和低频（5 Hz 或 1 Hz）刺激。通过测序与 Argonaute-2 结合的小 RNA，立即在 VHC-DBS 后和 97 天记录期间鉴定了功能 microRNAs，Argonaute-2 是 microRNA 沉默复合物的一个组成部分。
结果
低频 VHC-DBS 可使 PPS 模型中的首次自发性复发性癫痫发作潜伏期延长约 300%，从 19 天延长至 56 天。其他刺激方案均未改变潜伏期阶段。在癫痫发生过程中上调的 5 个 microRNAs 被 VHC 刺激抑制。
结论
我们得出结论，VHC-DBS 可延迟大鼠 PPS 模型中的癫痫发作，并与几种 microRNAs 的差异调节有关。需要进一步研究以确定 VHC 调节的 microRNAs 是否在该 DBS 模型的抗癫痫作用中起因果作用。
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