title: Brivaracetam augments short-term depression and slows vesicle recycling.
abstract: OBJECTIVE
  Brivaracetam (BRV) decreases seizure activity in a number of epilepsy models and binds to the synaptic vesicle glycoprotein 2A (SV2A) with a higher affinity than the antiepileptic drug levetiracetam (LEV). Experiments were performed to determine if BRV acted similarly to LEV to induce or augment short-term depression (STD) under high-frequency neuronal stimulation and slow synaptic vesicle recycling.
  
  
  METHODS
  Electrophysiologic field excitatory postsynaptic potential (fEPSP) recordings were made from CA1 synapses in rat hippocampal slices loaded with BRV or LEV during intrinsic activity or with BRV actively loaded during hypertonic stimulation. STD was examined in response to 5 or 40 Hz stimulus trains. Presynaptic release of FM1-43 was visualized using two-photon microscopy to assess drug effects upon synaptic vesicle mobilization.
  
  
  RESULTS
  When hippocampal slices were incubated in 0.1-30 μm BRV or 30 μm-1 mm LEV for 3 h, the relative CA1 field EPSPs decreased over the course of a high-frequency train of stimuli more than for control slices. This STD was frequency- and concentration-dependent, with BRV being 100-fold more potent than LEV. The extent of STD depended on the length of the incubation time for both drugs. Pretreatment with LEV occluded the effects of BRV. Repeated hypertonic sucrose treatments and train stimulation successfully unloaded BRV from recycling vesicles and reversed BRVs effects on STD, as previously reported for LEV. At their maximal concentrations, BRV slowed FM1-43 release to a greater extent than in slices loaded with LEV during prolonged stimulation.
  
  
  CONCLUSIONS
  BRV, similar to LEV, entered into recycling synaptic vesicles and produced a frequency-dependent decrement of synaptic transmission at 100-fold lower concentrations than LEV. In addition, BRV slowed synaptic vesicle mobilization more effectively than LEV, suggesting that these drugs may modify multiple functions of the synaptic vesicle protein SV2A to curb synaptic transmission and limit epileptic activity.
authors.affiliation: Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota, U.S.A.|Electrophysiology Laboratory, Xuanwu Hospital, Capital Medical University, Beijing, China.|Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota, U.S.A.
authors.forename: Joseph
authors.initials: J
authors.lastname: Bognar
authors.affiliation: Department of Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota, U.S.A.
authors.forename: Tianyu
authors.initials: T
authors.lastname: He
authors.affiliation: Department of Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota, U.S.A.
authors.forename: Mouhari
authors.initials: M
authors.lastname: Mohammed
authors.affiliation: UCB Pharma S.A., Braine-l'Alleud, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Niespodziany
authors.affiliation: UCB Pharma S.A., Braine-l'Alleud, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Wolff
authors.affiliation: Department of Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota, U.S.A.
authors.forename: Manuel
authors.initials: M
authors.lastname: Esguerra
authors.affiliation: Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota, U.S.A.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rothman
authors.affiliation: Department of Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota, U.S.A.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Dubinsky
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D000077287:Levetiracetam; D008297:Male; D008856:Microscopy, Fluorescence; D010889:Piracetam / Q000031:analogs & derivatives / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013572:Synaptic Vesicles / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D011760:Pyrrolidinones; D000077287:Levetiracetam; C482793:brivaracetam; D010889:Piracetam
keywords: Anticonvulsants; Antiepileptic drugs; Brivaracetam; Epilepsy; Levetiracetam; SV2A; Short-term depression; Synaptic vesicle recycling