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

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.

• Authors: 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
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 56 Issue 3 Pg. 1825-1840 (Mar 2019) ISSN: 1559-1182 [Electronic] United States
• PMID: 29934763 (Publication Type: Journal Article)

Chemical References

• Anticonvulsants
• Pilocarpine
• Fingolimod Hydrochloride
• Kainic Acid

Topics

• Animals
• Anticonvulsants (therapeutic use)
• Disease Models, Animal
• Epilepsy, Temporal Lobe (chemically induced, drug therapy)
• Fingolimod Hydrochloride (therapeutic use)
• Kainic Acid
• Male
• Mice
• Pilocarpine
• Seizures (chemically induced, drug therapy)