Blumenfeld Hal, Klein Joshua P, Schridde Ulrich, Vestal Matthew, Rice Timothy, Khera Davender S, Bashyal Chhitij, Giblin Kathryn, Paul-Laughinghouse Crystal, Wang Frederick, Phadke Anuradha, Mission John, Agarwal Ravi K, Englot Dario J, Motelow Joshua, Nersesyan Hrachya, Waxman Stephen G, Levin April R
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520-8018, USA.
Epilepsia. 2008 Mar;49(3):400-9. doi: 10.1111/j.1528-1167.2007.01458.x. Epub 2007 Dec 6.
Current treatments for epilepsy may control seizures, but have no known effects on the underlying disease. We sought to determine whether early treatment in a model of genetic epilepsy would reduce the severity of the epilepsy phenotype in adulthood.
We used Wistar albino Glaxo rats of Rijswijk (WAG/Rij) rats, an established model of human absence epilepsy. Oral ethosuximide was given from age p21 to 5 months, covering the usual period in which seizures develop in this model (age approximately 3 months). Two experiments were performed: (1) cortical expression of ion channels Nav1.1, Nav1.6, and HCN1 (previously shown to be dysregulated in WAG/Rij) measured by immunocytochemistry in adult treated rats; and (2) electroencephalogram (EEG) recordings to measure seizure severity at serial time points after stopping the treatment.
Early treatment with ethosuximide blocked changes in the expression of ion channels Nav1.1, Nav1.6, and HCN1 normally associated with epilepsy in this model. In addition, the treatment led to a persistent suppression of seizures, even after therapy was discontinued. Thus, animals treated with ethosuximide from age p21 to 5 months still had a marked suppression of seizures at age 8 months.
These findings suggest that early treatment during development may provide a new strategy for preventing epilepsy in susceptible individuals. If confirmed with other drugs and epilepsy paradigms, the availability of a model in which epileptogenesis can be controlled has important implications both for future basic studies, and human therapeutic trials.
目前的癫痫治疗方法或许能控制癫痫发作，但对潜在疾病尚无已知疗效。我们试图确定在遗传性癫痫模型中进行早期治疗是否会减轻成年期癫痫表型的严重程度。
我们使用了里耶斯维克白化Wistar大鼠（WAG/Rij大鼠），这是一种公认的人类失神癫痫模型。从出生后21天至5个月给予口服乙琥胺，涵盖该模型中癫痫发作通常出现的时期（约3个月龄）。进行了两项实验：（1）通过免疫细胞化学法检测成年期接受治疗大鼠大脑皮层中离子通道Nav1.1、Nav1.6和HCN1的表达（先前已证明在WAG/Rij大鼠中这些离子通道表达失调）；（2）在停止治疗后的连续时间点进行脑电图（EEG）记录以测量癫痫发作的严重程度。
早期使用乙琥胺治疗可阻止该模型中通常与癫痫相关的离子通道Nav1.1、Nav1.6和HCN1表达的变化。此外，即使在治疗停止后，该治疗仍能持续抑制癫痫发作。因此，从出生后21天至5个月接受乙琥胺治疗的动物在8个月龄时癫痫发作仍受到显著抑制。
这些发现表明，发育过程中的早期治疗可能为预防易感个体患癫痫提供一种新策略。如果在其他药物和癫痫模型中得到证实，那么一个能够控制癫痫发生的模型的存在对未来的基础研究和人类治疗试验都具有重要意义。
