title: Early treatment suppresses the development of spike-wave epilepsy in a rat model.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520-8018, USA. hal.blumenfeld@yale.edu
authors: Hal
authors: H
authors: Blumenfeld
authors: Joshua P
authors: JP
authors: Klein
authors: Ulrich
authors: U
authors: Schridde
authors: Matthew
authors: M
authors: Vestal
authors: Timothy
authors: T
authors: Rice
authors: Davender S
authors: DS
authors: Khera
authors: Chhitij
authors: C
authors: Bashyal
authors: Kathryn
authors: K
authors: Giblin
authors: Crystal
authors: C
authors: Paul-Laughinghouse
authors: Frederick
authors: F
authors: Wang
authors: Anuradha
authors: A
authors: Phadke
authors: John
authors: J
authors: Mission
authors: Ravi K
authors: RK
authors: Agarwal
authors: Dario J
authors: DJ
authors: Englot
authors: Joshua
authors: J
authors: Motelow
authors: Hrachya
authors: H
authors: Nersesyan
authors: Stephen G
authors: SG
authors: Waxman
authors: April R
authors: AR
authors: Levin
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000187:drug effects* / Q000706:statistics & numerical data; D004832:Epilepsy, Absence / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control*; D005013:Ethosuximide / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000187:drug effects / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics; D010641:Phenotype; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics
chemical_list: D000927:Anticonvulsants; D054815:Cyclic Nucleotide-Gated Cation Channels; C578665:HCN1 protein, human; C578667:Hcn1 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; C568242:SCN1A protein, human; C568250:Scn1a protein, rat; C507811:Scn8a protein, rat; D015222:Sodium Channels; D005013:Ethosuximide