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Early treatment suppresses the development of spike-wave epilepsy in a rat model

  1. Hal Blumenfeld1,2,3,
  2. Joshua P. Klein1,
  3. Ulrich Schridde1,
  4. Matthew Vestal1,
  5. Timothy Rice1,
  6. Davender S. Khera1,
  7. Chhitij Bashyal1,
  8. Kathryn Giblin1,
  9. Crystal Paul-Laughinghouse1,
  10. Frederick Wang1,
  11. Anuradha Phadke1,
  12. John Mission1,
  13. Ravi K. Agarwal1,
  14. Dario J. Englot1,
  15. Joshua Motelow1,
  16. Hrachya Nersesyan1,
  17. Stephen G. Waxman1,
  18. April R. Levin1

Article first published online: 7 DEC 2007

DOI: 10.1111/j.1528-1167.2007.01458.x

Issue

Epilepsia

Epilepsia

Volume 49, Issue 3, pages 400–409, March 2008

Additional Information

How to Cite

Blumenfeld, H., Klein, J. P., Schridde, U., Vestal, M., Rice, T., Khera, D. S., Bashyal, C., Giblin, K., Paul-Laughinghouse, C., Wang, F., Phadke, A., Mission, J., Agarwal, R. K., Englot, D. J., Motelow, J., Nersesyan, H., Waxman, S. G. and Levin, A. R. (2008), Early treatment suppresses the development of spike-wave epilepsy in a rat model. Epilepsia, 49: 400–409. doi: 10.1111/j.1528-1167.2007.01458.x

Author Information

  1. 1

    Neurology

  2. 2

    Neurobiology

  3. 3

    Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, U.S.A.

*Address correspondence to Hal Blumenfeld, MD, PhD, Yale Departments of Neurology, Neurobiology, and Neurosurgery, 333 Cedar Street, New Haven, CT 06520-8018, U.S.A. E-mail: hal.blumenfeld@yale.edu

Publication History

  1. Issue published online: 7 DEC 2007
  2. Article first published online: 7 DEC 2007
  3. Accepted October 24, 2007; Online Early publication December 10, 2007.

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Keywords:

  • Epileptogenesis;
  • Activity-dependent;
  • Prevention;
  • Idiopathic generalized epilepsy;
  • Sodium channels;
  • HCN1

Summary

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 ∼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.

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