Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rio Grande do Sul, Brazil.
Brain Res. 2012 Sep 20;1474:110-7. doi: 10.1016/j.brainres.2012.07.046. Epub 2012 Aug 3.
Status epilepticus (SE) when occurred during brain development can cause short- and long-term consequences, which are frequently associated with NMDA-mediated glutamatergic excitotoxicity. In the present work, we investigated the putative neuroprotective role of ketamine, an NMDA receptor antagonist, on early life SE-induced acute neuronal death and long-term behavioral abnormalities. Male Wistar rats (16 postnatal days) were induced to SE by LiCl-pilocarpine i.p. administration (3 mEq/kg; 60 mg/kg, respectively). Fifteen or 60min after pilocarpine injection, animals received a ketamine administration (22.5mg/kg i.p.). Neuronal degeneration was assessed 24h after SE induction. Another subset of animals was destined to behavioral tasks in adulthood (75-80 postnatal days). Fluoro-Jade C labeling revealed a marked neuronal death on CA1 hippocampal subfield, habenula, thalamus and amygdala in SE animals. Ketamine post-SE onset treatment prevented neuronal death in all regions assessed. In the elevated plus maze, SE induced an increase in anxiety-like behaviors whereas ketamine administration during seizures was able to prevent this alteration. Ketamine administration in non-SE animals resulted in high anxiety levels. There were no observed differences among groups in the open field task in all parameters analyzed. Our results suggest that ketamine post-SE onset treatment was effective in preventing acute and long-standing alterations caused by SE early in life, which indicates a putative role of glutamatergic system on SE-induced brain damage as well as long-lasting behavioral consequences.
癫痫持续状态（SE）在大脑发育过程中发生时会导致短期和长期的后果，这通常与 NMDA 介导的谷氨酸能兴奋性毒性有关。在本工作中，我们研究了氯胺酮（一种 NMDA 受体拮抗剂）在生命早期 SE 诱导的急性神经元死亡和长期行为异常中的潜在神经保护作用。雄性 Wistar 大鼠（出生后 16 天）通过腹腔内给予氯化锂-毛果芸香碱（3 mEq/kg；60mg/kg）诱导 SE。毛果芸香碱注射后 15 或 60min，动物接受氯胺酮（22.5mg/kg 腹腔内注射）治疗。SE 诱导后 24h 评估神经元变性。另一组动物在成年期（出生后 75-80 天）进行行为任务。氟-Jade C 标记显示 SE 动物 CA1 海马亚区、缰核、丘脑和杏仁核有明显的神经元死亡。SE 后发作时给予氯胺酮治疗可预防所有评估区域的神经元死亡。在高架十字迷宫中，SE 诱导焦虑样行为增加，而在癫痫发作期间给予氯胺酮治疗能够预防这种改变。在非 SE 动物中给予氯胺酮会导致高焦虑水平。在所有分析的参数中，各组在旷场任务中均未观察到差异。我们的结果表明，SE 后发作时给予氯胺酮治疗可有效预防生命早期 SE 引起的急性和长期改变，这表明谷氨酸能系统在 SE 诱导的脑损伤以及长期行为后果中起作用。
