Mechanism of Action of Levetiracetam (Keppra)
Levetiracetam exerts its antiepileptic effect primarily through binding to synaptic vesicle protein 2A (SV2A), which modulates neurotransmitter release and prevents hypersynchronization of epileptiform activity. 1, 2
Primary Mechanism: SV2A Binding
Levetiracetam binds stereoselectively to synaptic vesicle protein 2A (SV2A), a protein involved in regulating vesicle exocytosis, representing a novel class of anticonvulsant action distinct from traditional antiepileptic drugs. 1, 2
The binding affinity to SV2A correlates directly with antiseizure potency in animal models, suggesting this interaction is central to the drug's therapeutic mechanism. 2
Levetiracetam requires vesicular entry to reach its intravesicular SV2A binding site, which explains why the drug requires synaptic activity and a prolonged incubation period for full effect. 3
Functional Effects on Neurotransmission
Levetiracetam reduces the readily releasable pool of synaptic vesicles and decreases neurotransmitter release in a frequency-dependent manner, preferentially affecting rapidly firing neurons characteristic of seizure activity. 3
The drug selectively inhibits burst firing and hypersynchronization of epileptiform activity without affecting normal neuronal excitability, allowing it to prevent seizure propagation while preserving physiologic brain function. 2
Levetiracetam modulates SV2A protein interactions, including effects on synaptotagmin (a calcium-sensor protein), which may contribute to its ability to normalize aberrant neurotransmission. 4
Additional Mechanisms
Levetiracetam partially inhibits N-type calcium currents in neuronal cells, providing an additional mechanism for reducing excessive neurotransmitter release. 2, 5
The drug opposes the activity of negative modulators of GABA- and glycine-gated currents, though it does not directly facilitate GABAergic neurotransmission like traditional antiepileptics. 2, 5
Levetiracetam inhibits calcium release from intraneuronal stores, further contributing to its ability to dampen excessive neuronal activity. 5
What Levetiracetam Does NOT Do (Important Distinction)
Unlike benzodiazepines and other traditional antiepileptics, levetiracetam does not bind to GABA, benzodiazepine, glycine, or NMDA receptors, and does not affect voltage-gated sodium channels or T-type calcium currents. 2
This unique mechanism explains why levetiracetam has minimal impact on arousal function and does not cause cognitive impairment at therapeutic doses (500-2000 mg/day), unlike GABA-ergic drugs. 1, 6
Clinical Implications of the Mechanism
The SV2A-mediated mechanism provides broad-spectrum efficacy across partial-onset seizures, myoclonic seizures, and generalized tonic-clonic seizures. 6
The frequency-dependent effect means levetiracetam has its most marked impact on rapidly discharging neurons during seizure activity, providing selectivity for pathologic versus physiologic neuronal firing. 3
Chronic treatment with levetiracetam dose-dependently prevents the development of hippocampal hyperexcitability following status epilepticus, suggesting potential antiepileptogenic and disease-modifying properties beyond acute seizure suppression. 7