A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam

Abstract

A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam. J Neurophysiol 106: 1227-1239, 2011. First published June 8, 2011 doi:10.1152/jn.00279.2011 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.epilepsy; synaptic vesicle protein 2A; synaptic vesicle release; hippocampal slice LEVETIRACETAM (LEV) IS AN antiepileptic drug (AED) with a unique mode of action and efficacy against focal and generalized seizures. The exact mechanism by which this drug reduces seizures is still under investigation. LEV does not inhibit voltage-gated Na ϩ channels (Zona et al. 2001), nor does it modulate GABA receptors (Margineanu and Klitgaard 2003), two common AED mechanisms. It is established that LEV binds to a presynaptic protein, synaptic vesicle protein 2A (SV2A), located in the membrane of synaptic vesicles (Lynch et al. 2004). The precise function of SV2A is also unknown, but studies of cultured neurons from SV2A knockout mice show a reduced postsynaptic response, due to a lower initial vesicle release probability (Custer et al. 2006) and a decrease in the total amount of neurotransmitter release during a stimulus train compared with controls (Chang and Sudhof 2009).Because SV2A plays a modulatory, but not essential, role in neurotransmission, it is unclear how a ligand binding to SV2A might alter neurotransmitter release.The cellular mechanism of action of LEV remains paradoxical. While it seems to do nothing to normal synaptic transmission, i...

The Human Synaptic Vesicle Protein, SV2A, Functions as a Galactose Transporter in Saccharomyces cerevisiae

“…It was also shown that the antiepileptic efficacy of levetiracetam and its derivatives correlated with their binding affinity to SV2A (7). Levetiracetam reduces presynaptic glutamate release particularly in neurons with a sustained and high frequency firing (8,9). A neuroprotective role of SV2A modulation was also suggested by a recent study demonstrating that levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in a mouse model of Alzheimer disease (27).…”

“…Expressing Human SV2A-The antiepileptic drug levetiracetam specifically binds to SV2A and modulates its function (7)(8)(9). We found that the growth of hSV2A-expressing, hexose transport-deficient yeast cells on 2% galactose-containing medium was concentration-dependently inhibited by levetiracetam (Fig.…”

“…SV2A was identified as the specific binding site for levetiracetam, a second generation antiepileptic drug (7). Levetiracetam reduces presynaptic glutamate release particularly in neurons with a sustained and high frequency firing (7)(8)(9), and it was shown that the antiepileptic efficacy of levetiracetam and its derivatives correlates with their binding affinity to SV2A (7). SV2 has 12 transmembrane domains, and the N-terminal half of the protein shows significant amino acid sequence identity to a family of bacterial proteins that transport sugars, citrate, and drugs (1), and also to mammalian glucose transporters (1,10).…”

Levetiracetam improves symptoms of multiple chemical sensitivity: Case report

“…The mechanisms are paradoxical ; the amplitudes of the late postsynaptic field potentials are decreased for hyperactive synapses, with minimal effect on normal synaptic transmission (7). Recent studies also showed that levetiracetam has antioxidant property (8,9), and inhibits NO level (10).…”

Conformational Preference and Spectroscopical Characteristics of the Active Pharmaceutical Ingredient Levetiracetam

“…10 Its mechanism of action is distinct from that of the other antiepileptic drugs, [11][12][13][14] being presumed that it acts by modulating the function of the synaptic vesicle glycoprotein SV2A. [14][15][16][17][18][19][20][21][22] Its interesting pharmacokinetic properties together with its distinct chemical structure and mechanism of action make LEV unique among the marketed antiepileptic drugs. 9,11,23,24 For a better understanding of the pharmacodynamics of LEV, the characterization of its structure in solid and liquid state is crucial.…”