Mechanism of Action of Levetiracetam
Levetiracetam exerts its antiepileptic effect primarily by binding to synaptic vesicle protein 2A (SV2A), which modulates neurotransmitter release and inhibits hypersynchronized neuronal activity, distinguishing it from traditional antiepileptic drugs that target ion channels or GABA receptors. 1
Primary Mechanism: SV2A Binding
Levetiracetam binds selectively and with high affinity to synaptic vesicle protein 2A (SV2A), a glycoprotein involved in the regulation of vesicle exocytosis and presynaptic neurotransmitter release 1, 2
The rank order of affinity for SV2A among levetiracetam analogs correlates directly with their antiseizure potency in animal models, suggesting this interaction is central to its therapeutic effect 1
This binding mechanism is unique among antiepileptic drugs and represents a novel class of anticonvulsant action 3
Secondary Mechanisms
Neuronal Activity Modulation
Levetiracetam selectively prevents hypersynchronization of epileptiform burst firing and propagation of seizure activity without affecting normal neuronal excitability 1
In vitro and in vivo recordings demonstrate that levetiracetam inhibits burst firing in the hippocampus while preserving baseline neuronal function 1
Calcium Channel Effects
Levetiracetam partially inhibits N-type calcium channels in neuronal cells, reducing calcium-mediated neurotransmitter release 1, 4
The drug also inhibits calcium release from intraneuronal stores, contributing to its anticonvulsant properties 5, 4
GABA and Glycine Modulation
Levetiracetam opposes the activity of negative modulators of GABA- and glycine-gated currents, indirectly enhancing inhibitory neurotransmission 1, 5, 4
Importantly, levetiracetam does not directly facilitate GABAergic neurotransmission, distinguishing it from benzodiazepines and barbiturates 1
What Levetiracetam Does NOT Do
Absence of Traditional Mechanisms
Levetiracetam does not bind to benzodiazepine, GABA, glycine, or NMDA receptors at concentrations up to 10 µM 1
It does not affect voltage-gated sodium channels or T-type calcium currents, unlike most traditional antiepileptic drugs 1
Levetiracetam lacks cytochrome P450 enzyme-inducing potential, resulting in minimal drug-drug interactions 5, 4
Clinical Implications of Mechanism
Functional Effects
As an SV2A modulator, levetiracetam has less impact on arousal function compared to benzodiazepines 3
Studies show no significant impairment of arousal or cognitive functions at therapeutic doses (500-2000 mg/day), with some studies demonstrating cognitive improvement 3
Specific Clinical Application
- The SV2A binding mechanism may be particularly relevant in STXBP1-related epilepsies, where the same synaptic vesicle release machinery is impaired, potentially allowing levetiracetam to specifically reverse disease-related epileptogenic abnormalities 6
Important Caveats
While the SV2A binding is well-established, the precise molecular significance of this interaction in producing antiepileptic effects remains incompletely understood 1
Levetiracetam demonstrates efficacy in chronic epilepsy models but minimal activity in acute seizure models, suggesting different mechanisms may operate acutely versus chronically 7
The drug's unique profile means it modulates pathological hypersynchronization without suppressing normal neuronal activity, explaining its favorable cognitive profile compared to older antiepileptic drugs 1