神经外科机器人系统辅助下经海马和杏仁核内注射海人酸建立新型恒河猴颞叶癫痫模型。
Establishment of a novel mesial temporal lobe epilepsy rhesus monkey model via intra-hippocampal and intra-amygdala kainic acid injection assisted by neurosurgical robot system.
机构信息
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
Department of Functional Neurosurgery, Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China.
出版信息
Brain Res Bull. 2019 Jul;149:32-41. doi: 10.1016/j.brainresbull.2019.04.002. Epub 2019 Apr 4.
BACKGROUND
Mesial temporal lobe epilepsy (mTLE) is the most common type of refractory epilepsy, and non-human primate (NHP) models are important to investigate its mechanism and therapy. However, previous mTLE-NHP models have some defects.
METHODS
Thirteen rhesus monkeys were randomly assigned to a control group and epilepsy group. Kainic acid (KA) was injected into the left hippocampus and amygdala assisted by a neurosurgical robot system, while the control group received normal saline injection. Stereoelectroencephalography (SEEG) electrodes were implanted into the hippocampus in the acute and chronic stages to monitor epileptic discharges, with continuous behavior monitoring. The changes in hippocampal volume were evaluated by magnetic resonance imaging. Transmission electron microscopy, western blotting and immunofluorescence were performed 3 months after injection to investigate neuronal ultrastructural alteration, blood-brain barrier (BBB) disruption, neuronal loss and gliosis in multiple brain regions.
RESULTS
In the epilepsy group, status epilepticus (SE) and spontaneously recurrent seizures (SRSs) were detected in the acute and chronic stages via video monitoring. SEEG confirmed that the epileptic zone was focused on the injection area. The hippocampal volume was significantly decreased in the chronic stage compared with baseline. Neuronal ultrastructure and BBB integrity deteriorated in the hippocampus and amygdala of epileptic monkeys. The obvious neuronal loss and gliosis in the CA1-CA4 hippocampal regions were confirmed by western blotting and immunofluorescence; however, the temporal cortex was not affected. Moreover, the neuronal ultrastructural deterioration was detected in other limbic system regions (orbitofrontal cortex and posterior cingulate cortex).
CONCLUSION
A novel mTLE-NHP model was induced by one-time intra-hippocampal and intra-amygdalar KA injection, with detectable SE and SRS. Severe hippocampal atrophy, neuronal ultrastructural damage, BBB disruption, neuronal loss and gliosis were confirmed in this model, with widespread limbic system damage, which are similar to the pathology of mTLE patients.
背景
颞叶内侧癫痫（mTLE）是最常见的难治性癫痫类型，非人类灵长类动物（NHP）模型对于研究其发病机制和治疗方法非常重要。然而，以前的 mTLE-NHP 模型存在一些缺陷。
方法
13 只恒河猴随机分为对照组和癫痫组。在神经外科机器人系统的辅助下，将海人酸（KA）注射到左侧海马和杏仁核，对照组注射生理盐水。在急性期和慢性期将立体脑电图（SEEG）电极植入海马，以监测癫痫发作，并进行连续行为监测。通过磁共振成像评估海马体积的变化。注射后 3 个月，通过透射电镜、western blot 和免疫荧光技术，研究多个脑区神经元超微结构改变、血脑屏障（BBB）破坏、神经元丢失和神经胶质增生。
结果
在癫痫组，通过视频监测发现急性期和慢性期有癫痫持续状态（SE）和自发性反复发作（SRS）。SEEG 证实癫痫灶集中在注射区。与基线相比，慢性期海马体积明显减小。癫痫猴海马和杏仁核的神经元超微结构和 BBB 完整性恶化。western blot 和免疫荧光证实 CA1-CA4 海马区有明显的神经元丢失和神经胶质增生；而颞叶皮质不受影响。此外，还检测到其他边缘系统区域（眶额皮质和后扣带回皮质）的神经元超微结构恶化。
结论
通过一次性海马内和杏仁核内 KA 注射诱导新型 mTLE-NHP 模型，可检测到 SE 和 SRS。该模型证实了严重的海马萎缩、神经元超微结构损伤、BBB 破坏、神经元丢失和神经胶质增生，以及广泛的边缘系统损伤，与 mTLE 患者的病理相似。
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