中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2019, Vol. 14 ›› Issue (3): 480-484.doi: 10.4103/1673-5374.245475

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

丙戊酸可抑制惊厥持续状态诱导的异常神经发生

  

  • 收稿日期:2018-06-23 修回日期:2018-09-06 出版日期:2019-03-15 发布日期:2019-03-15
  • 基金资助:

    中国国家自然科学基金项目青年项目（81201507）

Sodium valproate suppresses abnormal neurogenesis induced by convulsive status epilepticus

Peng Wu 1 , Yue Hu 1 , Xiu-Juan Li 1 , Min Cheng 1 , Li Jiang 1, 2, 3, 4   

  1. 1 Department of Neurology, Children’s Hospital of Chongqing Medical University, Chongqing, China
    2 Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China
    3 Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
    4 Key Laboratory of Pediatrics in Chongqing, Chongqing, China
  • Received:2018-06-23 Revised:2018-09-06 Online:2019-03-15 Published:2019-03-15
  • Contact: Li Jiang, MD, jiangli_99@126.com.
  • Supported by:

    This study was supported by the National Natural Science Foundation of China for Youth Science Project, No. 81201507 (to PW)

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摘要：

既往研究发现，惊厥持续状态在造成大量神经元死亡的同时能激活海马脑区神经干细胞的增殖，尤以齿状回颗粒下层与脑室管膜下区显著，同时增殖的干细胞具有向惊厥性脑损伤明显的区域迁移的趋势。作者既往研究结果也明确证实了丙戊酸对惊厥性癫痫持续状态大鼠认知功能的影响。神经发生是否可在丙戊酸的抗癫痫作用中起作用目前仍然未知。实验通过对Wistar大鼠腹腔内注射3 mEq/kg氯化锂并在18-20h后腹腔注射毛果芸香碱40 mg/kg建立惊厥持续状态模型，然后灌胃丙戊酸100，200，300，400，500，600mg/kg，每天6次(间隔4h)，持续5d，然后测量血浆中丙戊酸的浓度，发现300mg/kg丙戊酸干预的惊厥持续状态大鼠血浆中丙戊酸的有效浓度可达82.26±11.23μg/mL，因而以300mg/kg丙戊酸作为后续丙戊酸的干预浓度。可见下述变化：(1)以记录电极记录CA1区场兴奋性突触后电位见高频刺激诱导长时程增强；(2)以免疫组化染色分析脑组织中BrdU阳性细胞数量，发现丙戊酸干预明显提高惊厥持续状态大鼠的长时程增强的诱发成功率及维持时间，减少了海马颗粒下区和脑室下区中新生神经元的数量，并抑制了新生神经元向齿状回迁移；(3)表明丙戊酸可有效抑制惊厥持续状态后神经干细胞和新生神经元的异常增殖和迁移，通过调节惊厥持续状态后的神经再生及迁移发挥改善学习记忆能力的作用。

orcid: 0000-0001-5800-4221(Li Jiang)

关键词: 惊厥持续状态, 丙戊酸, 长时程增强, 神经干细胞, 神经发生, 细胞迁移, 颗粒下区, 室下区, 神经再生

Abstract:

Status epilepticus has been shown to activate the proliferation of neural stem cells in the hippocampus of the brain, while also causing a large amount of neuronal death, especially in the subgranular zone of the dentate gyrus and the subventricular zone. Simultaneously, proliferating stem cells tend to migrate to areas with obvious damage. Our previous studies have clearly confirmed the effect of sodium valproate on cognitive function in rats with convulsive status epilepticus. However, whether neurogenesis can play a role in the antiepileptic effect of sodium valproate remains unknown. A model of convulsive status epilepticus was established in Wistar rats by intraperitoneal injection of 3 mEq/kg lithium chloride, and intraperitoneal injection of pilocarpine 40 mg/kg after 18–20 hours. Sodium valproate (100, 200, 300, 400, 500, or 600 mg/kg) was intragastrically administered six times every day (4-hour intervals) for 5 days. To determine the best dosage, sodium valproate concentration was measured from the plasma. The effective concentration of sodium valproate in the plasma of the rats that received the 300-mg/kg interven¬tion was 82.26 ± 11.23 μg/mL. Thus, 300 mg/kg was subsequently used as the intervention concentration of sodium valproate. The following changes were seen: Recording excitatory postsynaptic potentials in the CA1 region revealed high-frequency stimulation-induced long-term po¬tentiation. Immunohistochemical staining for BrdU-positive cells in the brain revealed that sodium valproate intervention markedly increased the success rate and the duration of induced long-term potentiation in rats with convulsive status epilepticus. The intervention also reduced the number of newborn neurons in the subgranular area of the hippocampus and subventricular zone and inhibited the migration of newborn neu¬rons to the dentate gyrus. These results indicate that sodium valproate can effectively inhibit the abnormal proliferation and migration of neural stem cells and newborn neurons after convulsive status epilepticus, and improve learning and memory ability.

Key words: nerve regeneration, status epilepticus, sodium valproate, long-term potentiation, neural stem cells, neurogenesis, migration, subgranular zone, subventricular zone, neural regeneration