title: Lacosamide modulates interictal spiking and high-frequency oscillations in a model of mesial temporal lobe epilepsy.
abstract: OBJECTIVE
  Nearly one third of patients presenting with mesial temporal lobe epilepsy (MTLE), the most prevalent lesion-related epileptic disorder in adulthood, do not respond to currently available antiepileptic medications. Thus, there is a need to identify and characterize new antiepileptic drugs. In this study, we used the pilocarpine model of MTLE to establish the effects of a third generation drug, lacosamide (LCM), on seizures, interictal spikes and high-frequency oscillations (HFOs, ripples: 80-200 Hz, fast ripples: 250-500 Hz).
  
  
  METHODS
  Sprague-Dawley rats (250-300 g) were injected with pilocarpine to induce a status epilepticus (SE) that was pharmacologically terminated after 1h. Eight pilocarpine-treated rats were then injected with LCM (30 mg/kg, i.p.) 4h after SE and daily for 14 days. Eight pilocarpine-treated rats were used as controls and treated with saline. Three days after SE, all rats were implanted with bipolar electrodes in the hippocampal CA3 region, entorhinal cortex (EC), dentate gyrus (DG) and subiculum and EEG-video monitored from day 4 to day 14 after SE.
  
  
  RESULTS
  LCM-treated animals showed lower rates of seizures (0.21 (± 0.11) seizures/day) than controls (2.6 (±0.57), p<0.05), and a longer latent period (LCM: 11 (± 1) days, controls: 6.25 (± 1), p<0.05). Rates of interictal spikes in LCM-treated rats were significantly lower than in controls in CA3 and subiculum (p<0.05). Rates of ripples and fast ripples associated with interictal spikes in CA3 and subiculum as well as rates of fast ripples occurring outside of interictal spikes in CA3 were also significantly lower in LCM-treated animals. In controls, interictal spikes and associated HFOs correlated to seizure clustering, while this was not the case for isolated HFOs.
  
  
  CONCLUSIONS
  Our findings show that early treatment with LCM has powerful anti-ictogenic properties in the pilocarpine model of MTLE. These effects are accompanied by decreased rates of interictal spikes and associated HFOs. Isolated HFOs were also modulated by LCM, in a manner that appeared to be unrelated to its antiictogenic effects. These results thus suggest that distinct mechanisms may underlie interictal-associated and isolated HFOs in the pilocarpine model of MTLE.
authors.affiliation: Montreal Neurological Institute and Department of Neurology & Neurosurgery, McGill University, 3801 University Street, Montréal, QC, Canada H3A 2B4.
authors.forename: Charles
authors.initials: C
authors.lastname: Behr
authors.affiliation: Montreal Neurological Institute and Department of Neurology & Neurosurgery, McGill University, 3801 University Street, Montréal, QC, Canada H3A 2B4.
authors.forename: Maxime
authors.initials: M
authors.lastname: Lévesque
authors.affiliation: Montreal Neurological Institute and Department of Neurology & Neurosurgery, McGill University, 3801 University Street, Montréal, QC, Canada H3A 2B4.
authors.forename: David
authors.initials: D
authors.lastname: Ragsdale
authors.affiliation: Montreal Neurological Institute and Department of Neurology & Neurosurgery, McGill University, 3801 University Street, Montréal, QC, Canada H3A 2B4. Electronic address: massimo.avoli@mcgill.ca.
authors.forename: Massimo
authors.initials: M
authors.lastname: Avoli
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004195:Disease Models, Animal; D000069280:Electrocorticography / Q000379:methods; D004567:Electrodes, Implanted; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy* / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D000078334:Lacosamide; D008297:Male; D010862:Pilocarpine; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy / Q000503:physiopathology; D013226:Status Epilepticus / Q000188:drug therapy / Q000503:physiopathology; D016896:Treatment Outcome; D014741:Video Recording / Q000379:methods
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D010862:Pilocarpine; D000078334:Lacosamide
keywords: Epilepsy; High-frequency oscillations; Hippocampus; Interictal spikes; Seizures