Treatment during a vulnerable developmental period rescues a genetic epilepsy
Treatment during a vulnerable developmental period rescues a genetic epilepsy
复制标题
DOI：
10.1038/nm.3987
复制
发表时间：
2015-12-01
期刊：
影响因子：
82.9
通讯作者：
Isbrandt, Dirk
中科院分区：
文献类型：
--
作者：
Marguet, Stephan Lawrence;Le-Schulte, Vu Thao Quyen;Isbrandt, Dirk
神经系统在特定的发育时期容易受到干扰。在这种敏感的时间窗口内受到侮辱可能会产生长期后果，包括癫痫等神经系统疾病的发展。在这里，我们报告说，在脆弱的新生儿期皮质发育的药理学干预的时间，防止病理遗传性癫痫模型。通过使用在人类新生儿癫痫综合征中突变的Kv 7电压门控K+通道功能障碍的小鼠，我们证明了钠-钾-氯化物协同转运蛋白NKCC 1拮抗剂布美他尼的安全性和有效性，该拮抗剂在出生后的前两周内给药。在Kv 7电流缺陷小鼠中，通常表现为癫痫，多动和刻板的成年人，短暂的布美他尼治疗使新生儿体内皮质网络和海马神经元活动正常化，防止海马结构损伤并恢复野生型成年人行为表型。此外，布美他尼治疗对对照小鼠没有不利影响。这些结果表明，在具有疾病易感性的个体中，在发育过程中的特定窗口中进行时间上安全的干预可以预防或阻止疾病进展。
The nervous system is vulnerable to perturbations during specific developmental periods. Insults during such susceptible time windows can have long-term consequences, including the development of neurological diseases such as epilepsy. Here we report that a pharmacological intervention timed during a vulnerable neonatal period of cortical development prevents pathology in a genetic epilepsy model. By using mice with dysfunctional Kv7 voltage-gated K+ channels, which are mutated in human neonatal epilepsy syndromes, we demonstrate the safety and efficacy of the sodium-potassium-chloride cotransporter NKCC1 antagonist bumetanide, which was administered during the first two postnatal weeks. In Kv7 current-deficient mice, which normally display epilepsy, hyperactivity and stereotypies as adults, transient bumetanide treatment normalized neonatal in vivo cortical network and hippocampal neuronal activity, prevented structural damage in the hippocampus and restored wild-type adult behavioral phenotypes. Furthermore, bumetanide treatment did not adversely affect control mice. These results suggest that in individuals with disease susceptibility, timing prophylactically safe interventions to specific windows during development may prevent or arrest disease progression.