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

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Background: Pharmacoresistance 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 Findings: In 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. Conclusion: This 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.
Publisher
PUBLIC LIBRARY SCIENCE
Issue Date
2014-01
Language
English
Article Type
Article
Keywords

TEMPORAL-LOBE EPILEPSY; RAT PILOCARPINE MODEL; ELEVATED PLUS-MAZE; STATUS EPILEPTICUS; SPONTANEOUS SEIZURES; PSYCHIATRIC COMORBIDITY; MULTIDRUG-RESISTANCE; ANTIEPILEPTIC DRUGS; REFRACTORY EPILEPSY; P-GLYCOPROTEIN

Citation

PLOS ONE, v.9, no.1

ISSN
1932-6203
DOI
10.1371/journal.pone.0085617
URI
http://hdl.handle.net/10203/189948
Appears in Collection
BiS-Journal Papers(저널논문)
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