PURPOSE: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.
PURPOSE: 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. METHODS: We used Wistar albino Glaxo rats of Rijswijk (WAG/Rij) rats, an established model of humanabsence 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. RESULTS: 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. DISCUSSION: 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.
Authors: Shlomo Shinnar; Avital Cnaan; Fengming Hu; Peggy Clark; Dennis Dlugos; Deborah G Hirtz; David Masur; Eli M Mizrahi; Solomon L Moshé; Tracy A Glauser Journal: Neurology Date: 2015-08-26 Impact factor: 9.910
Authors: Petra Ehling; Tatyana Kanyshkova; Arnd Baumann; Peter Landgraf; Sven G Meuth; Hans-Christian Pape; Thomas Budde Journal: J Mol Neurosci Date: 2012-04-25 Impact factor: 3.444
Authors: Amy R Brooks-Kayal; Kevin G Bath; Anne T Berg; Aristea S Galanopoulou; Gregory L Holmes; Frances E Jensen; Andres M Kanner; Terence J O'Brien; Vicky H Whittemore; Melodie R Winawer; Manisha Patel; Helen E Scharfman Journal: Epilepsia Date: 2013-08 Impact factor: 5.864
Authors: Tatyana Kanyshkova; Patrick Meuth; Pawan Bista; Zhiqiang Liu; Petra Ehling; Luigi Caputi; Michael Doengi; Dane M Chetkovich; Hans-Christian Pape; Thomas Budde Journal: Neurobiol Dis Date: 2011-09-16 Impact factor: 5.996