Anti-epileptogenic and Anti-convulsive Effects of Fingolimod in Experimental Temporal Lobe Epilepsy

Julika Pitsch, Julia C. Kuehn, Vadym Gnatkovsky, Johannes Alexander Müller, Karen M.J. van Loo, Marco de Curtis, Hartmut Vatter, Susanne Schoch, Christian E. Elger, Albert J. Becker

Research output: Contribution to journalArticle

Abstract

Temporal lobe epilepsy (TLE) represents a devastating neurological condition, in which approximately 4/5 of patients remain refractory for anti-convulsive drugs. Epilepsy surgery biopsies often reveal the damage pattern of “hippocampal sclerosis” (HS) characterized not only by neuronal loss but also pronounced astrogliosis and inflammatory changes. Since TLE shares distinct pathogenetic aspects with multiple sclerosis (MS), we have here scrutinized therapeutic effects in experimental TLE of the immunmodulator fingolimod, which is established in MS therapy. Fingolimod targets sphingosine-phosphate receptors (S1PRs). mRNAs of fingolimod target S1PRs were augmented in two experimental post status epilepticus (SE) TLE mouse models (suprahippocampal kainate/pilocarpine). SE frequently induces chronic recurrent seizures after an extended latency referred to as epileptogenesis. Transient fingolimod treatment of mice during epileptogenesis after suprahippocampal kainate-induced SE revealed substantial reduction of chronic seizure activity despite lacking acute attenuation of SE itself. Intriguingly, fingolimod exerted robust anti-convulsive activity in kainate-induced SE mice treated in the chronic TLE stage and had neuroprotective and anti-gliotic effects and reduced cytotoxic T cell infiltrates. Finally, the expression profile of fingolimod target-S1PRs in human hippocampal biopsy tissue of pharmacoresistant TLE patients undergoing epilepsy surgery for seizure relief suggests repurposing of fingolimod as novel therapeutic perspective in focal epilepsies.

Original languageEnglish
Pages (from-to)1-16
Number of pages16
JournalMolecular Neurobiology
DOIs
Publication statusAccepted/In press - Jun 22 2018

Keywords

  • Disease-modifying therapy
  • Epileptogenesis
  • Experimental epilepsy models
  • Temporal lobe epilepsy
  • Video-EEG

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

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  • Cite this

    Pitsch, J., Kuehn, J. C., Gnatkovsky, V., Müller, J. A., van Loo, K. M. J., de Curtis, M., Vatter, H., Schoch, S., Elger, C. E., & Becker, A. J. (Accepted/In press). Anti-epileptogenic and Anti-convulsive Effects of Fingolimod in Experimental Temporal Lobe Epilepsy. Molecular Neurobiology, 1-16. https://doi.org/10.1007/s12035-018-1181-y