title: A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam.
abstract: Levetiracetam (LEV) is one of the most commonly prescribed antiepileptic drugs, but its mechanism of action is uncertain. Based on prior information that LEV binds to the vesicular protein synaptic vesicle protein 2A and reduces presynaptic neurotransmitter release, we wanted to more rigorously characterize its effect on transmitter release and explain the requirement for a prolonged incubation period for its full effect to manifest. During whole cell patch recordings from rat hippocampal pyramidal neurons in vitro, we found that LEV decreased synaptic currents in a frequency-dependent manner and reduced the readily releasable pool of vesicles. When we manipulated spontaneous activity and stimulation paradigms, we found that synaptic activity during LEV incubation alters the time at which LEV's effect appears, as well as its magnitude. We believe that synaptic activity and concomitant vesicular release allow LEV to enter recycling vesicles to reach its binding site, synaptic vesicle protein 2A. In support of this hypothesis, a vesicular "load-unload" protocol using hypertonic sucrose in the presence of LEV quickly induced LEV's effect. The effect rapidly disappeared after unloading in the absence of LEV. These findings are compatible with LEV acting at an intravesicular binding site to modulate the release of transmitter and with its most marked effect on rapidly discharging neurons. Our results identify a unique neurobiological explanation for LEV's highly selective antiepileptic effect and suggest that synaptic vesicle proteins might be appropriate targets for the development of other neuroactive drugs.
authors.affiliation: Department of Neurology, University of Minnesota Medical School, 420 Delaware St., MMC 295, Minneapolis, MN 55455, USA.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Meehan
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Yang
authors.forename: Brian D
authors.initials: BD
authors.lastname: McAdams
authors.forename: Lilian
authors.initials: L
authors.lastname: Yuan
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rothman
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D000077287:Levetiracetam; D009924:Organ Culture Techniques; D010889:Piracetam / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; 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; D000077287:Levetiracetam; D010889:Piracetam