Early treatment suppresses the development of spike-wave epilepsy in a rat model.
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.
Blumenfeld
Hal
H
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520-8018, USA. hal.blumenfeld@yale.edu
Klein
Joshua P
JP
Schridde
Ulrich
U
Vestal
Matthew
M
Rice
Timothy
T
Khera
Davender S
DS
Bashyal
Chhitij
C
Giblin
Kathryn
K
Paul-Laughinghouse
Crystal
C
Wang
Frederick
F
Phadke
Anuradha
A
Mission
John
J
Agarwal
Ravi K
RK
Englot
Dario J
DJ
Motelow
Joshua
J
Nersesyan
Hrachya
H
Waxman
Stephen G
SG
Levin
April R
AR
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
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