Levetiracetam Has a Presynaptic Effect on Central Neurotransmission
Abstract number :
2.238
Submission category :
Antiepileptic Drugs-All Ages
Year :
2006
Submission ID :
6677
Source :
www.aesnet.org
Presentation date :
12/1/2006 12:00:00 AM
Published date :
Nov 30, 2006, 06:00 AM
Authors :
Xiao-Feng Yang, and Steven M. Rothman
Although levetiracetam (LEV) has established antiepileptic utility, there is still no convincing mechanistic data that account for its therapeutic success. Based upon recent binding experiments that show high affinity for SV2A, a synaptic vesicle protein, we decided to investigate the possibility that LEV inhibits neurotransmitter release., Imaging and electrophysiology experiments were carried out on 500 [mu]m thick rat hippocampal slices cut on a vibratome and maintined in a submerged perfusion chamber. A bipolar stimulating electrode was placed in the Schaffer collateral layer and evoked potentials were recorded in the dendritic layer of CA1. The synaptic vesicle label FM1-43 was imaged with a 2-photon microscope., When slices were exposed to LEV (100 [mu]M) for 30 minutes, we found no alteration of baseline evoked synaptic potentials nor any change in paired pulse potentiation (PPP). However, when slices were preincuabated in LEV for 3 hours, there was a significant, frequency and concentration dependent, reduction in both PPP and synaptic facilitation. At 40 and 80 Hz stimulation, 30 [mu]M LEV reduced PPP from 160% to 139% of control and 155% to 120% of control, respectively (n=8 slices). With 100 [mu]M LEV, stimulation frequencies as low as 5 Hz, reduced PPP from 125% to 110% of control (n=8 slices). With repetitive stimulation from 5-80 Hz, there was a progressive decrease in successive responses in LEV-treated (100 [mu]M) slices that was not seen in control slices. The figure below shows the effect of a series of pulses at 80 Hz, control slices are on top, LEV below.[figure1]When slices were incubated in ucb L060 (100 [mu]M), a LEV enantiomer lacking antiepileptic and SV2A binding activity, there was no effect on synaptic physiology. When slices were preincubed in FM1-43 and electrically stimulated to destain, there was a significant reduction in destaining rate in LEV (100 [mu]M) exposed slices, compared to control and enantiomer-exposed slices, suggesting that LEV inhibited some phase of vesicle release., Our data are most economically explained by a presynaptic effect of LEV on neurotransmitter release. It is possible that LEV directly blocks vesicle docking and that this effect is amplified at higher rates of stimulation. Alternatively, LEV could alter calcium buffering in presynaptic terminals or the actual flux of calcium into the terminals. Any of these mechanisms would be compatible with the known affinity of LEV for SV2A. LEV may require access to some intracellular compartment, explaining the necessity for a prolonged slice exposure., (Supported by the Alafi Family Foundation and the NIH (R01 NS042936 to SMR).)
Antiepileptic Drugs