Department of Human Genetics, Emory University, Atlanta, Georgia, 30322, USA.
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
Sci Rep. 2018 Jan 9;8(1):126. doi: 10.1038/s41598-017-17786-0.
We previously found that genetic mutants with reduced expression or activity of Scn8a are resistant to induced seizures and that co-segregation of a mutant Scn8a allele can increase survival and seizure resistance of Scn1a mutant mice. In contrast, Scn8a expression is increased in the hippocampus following status epilepticus and amygdala kindling. These findings point to Scn8a as a promising therapeutic target for epilepsy and raise the possibility that aberrant overexpression of Scn8a in limbic structures may contribute to some epilepsies, including temporal lobe epilepsy. Using a small-hairpin-interfering RNA directed against the Scn8a gene, we selectively reduced Scn8a expression in the hippocampus of the intrahippocampal kainic acid (KA) mouse model of mesial temporal lobe epilepsy. We found that Scn8a knockdown prevented the development of spontaneous seizures in 9/10 mice, ameliorated KA-induced hyperactivity, and reduced reactive gliosis. These results support the potential of selectively targeting Scn8a for the treatment of refractory epilepsy.
我们之前发现，Scn8a 表达或活性降低的遗传突变体对诱导性癫痫发作具有抗性，并且突变 Scn8a 等位基因的共分离可以提高 Scn1a 突变小鼠的存活率和癫痫发作抗性。相比之下，在癫痫持续状态和杏仁核点燃后，海马体中的 Scn8a 表达增加。这些发现表明 Scn8a 是癫痫治疗的一个有前途的靶点，并提出了异常过度表达 Scn8a 可能导致某些癫痫的可能性，包括颞叶癫痫。我们使用针对 Scn8a 基因的短发夹干扰 RNA，选择性地降低了内侧颞叶癫痫海马内海人酸 (KA) 小鼠模型中海马体中的 Scn8a 表达。我们发现 Scn8a 敲低可防止 9/10 只小鼠自发性癫痫发作的发展，改善 KA 诱导的过度活跃，并减少反应性神经胶质增生。这些结果支持选择性靶向 Scn8a 治疗难治性癫痫的潜力。
