Unique Behavioral Characteristics and microRNA Signatures in a Drug Resistant Epilepsy Model

Jangsup Moon,Sang Kun Lee,Jae-Jun Ban,Keun-Hwa Jung,Hyunwoo Yang,Daejong Jeon,Gwan-Su Yi,Jeong-Min Kim,Jung-Won Shin,Arshi Khalid,Kon Chu,Kyung-Il Park,Soon-Tae Lee,Jiye Choi,Ken Mills

doi:10.1371/journal.pone.0085617

Abstract

BackgroundPharmacoresistance is a major issue in the treatment of epilepsy. However, the mechanism underlying pharmacoresistance to antiepileptic drugs (AEDs) is still unclear, and few animal models have been established for studying drug resistant epilepsy (DRE). In our study, spontaneous recurrent seizures (SRSs) were investigated by video-EEG monitoring during the entire procedure.Methods/Principal FindingsIn the mouse pilocarpine-induced epilepsy model, we administered levetiracetam (LEV) and valproate (VPA) in sequence. AED-responsive and AED-resistant mice were naturally selected after 7-day treatment of LEV and VPA. Behavioral tests (open field, object exploration, elevated plus maze, and light-dark transition test) and a microRNA microarray test were performed. Among the 37 epileptic mice with SRS, 23 showed significantly fewer SRSs during administration of LEV (n = 16, LEV sensitive (LS) group) or VPA (n = 7, LEV resistant/VPA sensitive (LRVS) group), while 7 epileptic mice did not show any amelioration with either of the AEDs (n = 7, multidrug resistant (MDR) group). On the behavioral assessment, MDR mice displayed distinctive behaviors in the object exploration and elevated plus maze tests, which were not observed in the LS group. Expression of miRNA was altered in LS and MDR groups, and we identified 4 miRNAs (miR-206, miR-374, miR-468, and miR-142-5p), which were differently modulated in the MDR group versus both control and LS groups.ConclusionThis is the first study to identify a pharmacoresistant subgroup, resistant to 2 AEDs, in the pilocarpine-induced epilepsy model. We hypothesize that modulation of the identified miRNAs may play a key role in developing pharmacoresistance and behavioral alterations in the MDR group.

Highlights

Pharmacoresistance is a major issue in the treatment of epilepsy
We hypothesize that modulation of the identified miRNAs may play a key role in developing pharmacoresistance and behavioral alterations in the multidrug resistant (MDR) group
7 epileptic mice showed a significant reduction in the number of spontaneous recurrent seizures (SRSs) per day during VPA treatment (p,0.05; Table 1)

Summary

Introduction

Pharmacoresistance is a major issue in the treatment of epilepsy. About 30–40% of patients do not respond to treatment with different antiepileptic drugs (AEDs) [1,2,3]. The International League Against Epilepsy (ILAE) defines drug resistant epilepsy (DRE) as the ‘‘failure of adequate trials of two tolerated and appropriately chosen and used AED schedules to achieve sustained seizure freedom.’’ [4] the mechanisms underlying pharmacoresistance are unclear. The second group includes an AED resistant subgroup in an established epilepsy model [9,10,11]. Using these animal models, some mechanisms of pharmacoresistance have been identified [12]. The mechanism underlying pharmacoresistance to antiepileptic drugs (AEDs) is still unclear, and few animal models have been established for studying drug resistant epilepsy (DRE). Spontaneous recurrent seizures (SRSs) were investigated by video-EEG monitoring during the entire procedure

Methods

Results

Discussion

Conclusion