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

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.

microRNA‐139‐5p confers sensitivity to antiepileptic drugs in refractory epilepsy by inhibition of MRP1

“…An increasing number of studies have documented the potential roles of multiple miRNAs in epilepsy, which provided better understanding of the pathogenesis, treatment, and diagnosis . The current antiepileptic drugs have been proved to generate effects on the expression of miRNAs, and the characterization of these effects on the pharmacoresistance and behavioral alterations is clinically valuable . Additionally, abnormal changes in miRNA expression in the hippocampus of temporal lobe epilepsy and in neural tissues from animal models of epilepsy is clearly associated with neurotransmitter signaling, neuroinflammation, as well as transcription factors .…”

“…31,32 The current antiepileptic drugs have been proved to generate effects on the expression of miRNAs, and the characterization of these effects on the pharmacoresistance and behavioral alterations is clinically valuable. 33 Additionally, abnormal changes in miRNA expression in the hippocampus of temporal lobe epilepsy and in neural tissues from animal models of epilepsy is clearly associated with neurotransmitter signaling, neuroinflammation, as well as transcription factors. 9 Neuroprotective effects of miR-344a have been delineated in seizures, whereby an improvement in seizure behavior and a decrease in neurological impairments in the cortex in response to the treatment F I G U R E 3 MRP1 is a target of miR-139-5p.…”

Chemically-induced TLE models: Topical application

“…In several models, rodents can be divided into resistant and responder subsets by preliminary testing with frontline antiepileptic drugs (Löscher et al, 1993;Moon et al, 2014). Most of the work on separating rodents into responders and non-responders used systemic induction of SE or electrical kindling.…”

Dysregulation of long non-coding RNAs in mouse models of localization-related epilepsy

“…People with epilepsy have increased risk of psychosocial disorders, neurodegenerative conditions, and systemic diseases [2]. Multiple antiepileptic drugs (AEDs) have been developed for treatment of seizures, but 30e40% of epileptic patients remain refractory to treatment, and the search for more tolerable AEDs with improved pharmacokinetics has been ongoing [3,4]. Animal models of acute seizures such as maximal electroshock seizure (MES) and pentylenetetrazole (PTZ) models have widely been used for AED discovery, as these models are suitable for testing a large number of potentially anticonvulsant drugs in relatively short time [3].…”

“…Epigenetic regulatory mechanisms have been implicated in neural development, neural network function, and homeostasis, the processes that underlie the complex states of epileptic disorders [13]. As part of the diverse epigenetic regulatory processes that occur in the epileptic brain [4], lncRNAs are likely involved in modulating the molecular pathophysiology of epilepsy. Thus, identification of dysregulated lncRNAs in epilepsy and investigation into their potential functions might provide an important step towards developing drugs based on novel therapeutic targets.…”