Artikel
Large-scale gene expression analysis in hippocampal tissue of epileptic patients stratified according to levetiracetam responsiveness
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Veröffentlicht: | 11. September 2012 |
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Gliederung
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Focal epilepsies represent severe neurological disorders, which frequently originate in the temporal lobe (temporal lobe epilepsy; TLE). TLE is often associated with pharmacoresistance and in many TLE patients only neurosurgical removal of the seizure focus results in seizure control. Levetiracetam (LEV) represents a unique type of anti epileptic drug (AED) as it is the only one known so far whose high-affinity binding site, the synaptic vesicle protein SV2A, is a component of the presynaptic release machinery and as it generally leads to excellent seizure control even in previously refractory patients. However, a subgroup of LEV-treated TLE patients (approximately 20–30% of individuals) does not reveal any response to LEV from the beginning of treatment, i.e., a priori non-responders. This unexpected phenomenon is in contrast to the well known secondary, acquired pharmacoresistance that is observed in a high number of patients.
Using human hippocampal tissue derived from epilepsy surgery (n=52) we established a genome wide expression array analysis, which provides differential hippocampal gene expression patterns in LEV-responders versus a priori non-responders. Subsequent promoter analysis revealed individual single nucleotide polymorphisms (SNPs) that are strong candidates to influence the respective gene expression, for example of the molecule PIGP an elementary component of Wnt-signaling. Our results suggest distinct SNPs, transcription factors and presynapse-associated molecules as new factors in LEV-response of TLE patients, which will need further assessment as diagnostic markers or therapeutic targets in the future.
Our work is supported by DFG, BMBF, Else Kröner-Fresenius-Stiftung & BONFOR program of the University of Bonn Medical Center.