机构：[1]Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota, U.S.A.[2]Electrophysiology Laboratory, Xuanwu Hospital, Capital Medical University, Beijing, China首都医科大学宣武医院[3]Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing, China[4]Department of Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota, U.S.A.[5]UCB Pharma S.A., Braine-l’Alleud, Belgium
ObjectiveBrivaracetam (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. MethodsElectrophysiologic 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. ResultsWhen hippocampal slices were incubated in 0.1-30 m BRV or 30 m-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. SignificanceBRV, 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.
第一作者机构：[1]Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota, U.S.A.[2]Electrophysiology Laboratory, Xuanwu Hospital, Capital Medical University, Beijing, China[3]Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing, China
通讯作者：
通讯机构：[*1]Department of Neuroscience, University of Minnesota Medical School, 6-145 Jackson Hall, 321 Church St SE,Minneapolis,MN 55455, U.S.A
推荐引用方式(GB/T 7714)：
Xiaofeng Yang ,Joseph Bognar Jr ,Tianyu He ,et al.Brivaracetam augments short-term depression and slows vesicle recycling[J].EPILEPSIA.2015,56(12):1899-1909.doi:10.1111/epi.13223.
APA：
Xiaofeng Yang,,Joseph Bognar Jr,,Tianyu He,,Mouhari Mohammed,,Isabelle Niespodziany,...&Janet M. Dubinsky.(2015).Brivaracetam augments short-term depression and slows vesicle recycling.EPILEPSIA,56,(12)
医学