Unique behavioral characteristics and microRNA signatures in a drug resistant epilepsy model.
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.


RESULTS
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.


CONCLUSIONS
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.
Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
Jangsup
J
Moon
Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
Soon-Tae
ST
Lee
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
Jiye
J
Choi
Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
Keun-Hwa
KH
Jung
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
Hyunwoo
H
Yang
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
Arshi
A
Khalid
Department of Neurology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
Jeong-Min
JM
Kim
Department of Neurology, Seoul Paik Hospital, Inje University College of Medicine, Seoul, Republic of Korea.
Kyung-Il
KI
Park
Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
Jung-Won
JW
Shin
Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
Jae-Jun
JJ
Ban
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
Gwan-Su
GS
Yi
Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
Sang Kun
SK
Lee
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
Daejong
D
Jeon
Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
Kon
K
Chu
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004351:Drug Resistance; D004569:Electroencephalography; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D010862:Pilocarpine / Q000008:administration & dosage / Q000009:adverse effects
D000927:Anticonvulsants; D035683:MicroRNAs; D010862:Pilocarpine