Mechanism of Action of Keppra (Levetiracetam)
Keppra (levetiracetam) works primarily by binding to synaptic vesicle protein 2A (SV2A), which regulates neurotransmitter release, and this unique mechanism distinguishes it from traditional antiepileptic drugs that target sodium channels or GABA receptors. 1
Primary Mechanism: SV2A Binding
- Levetiracetam binds stereoselectively to synaptic vesicle protein 2A (SV2A), a protein involved in regulating vesicle exocytosis and neurotransmitter release 1, 2
- This binding affinity directly correlates with antiseizure potency across multiple epilepsy models, with correlation coefficients of r²=0.77-0.80 in audiogenic seizure, corneal kindling, and generalized absence epilepsy models 3
- The SV2A interaction appears to selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity without affecting normal neuronal excitability 1
Secondary Mechanisms
- Levetiracetam inhibits N-type calcium channels, reducing calcium-mediated neurotransmitter release 1, 4
- It inhibits calcium release from intraneuronal stores, further modulating synaptic transmission 5, 4
- The drug opposes the activity of negative modulators of GABA- and glycine-gated currents, indirectly enhancing inhibitory neurotransmission without directly facilitating GABAergic transmission 1, 6
What Levetiracetam Does NOT Do
- Does not bind to benzodiazepine, GABA, glycine, or NMDA receptors at concentrations up to 10 µM 1
- Does not affect neuronal voltage-gated sodium channels or T-type calcium currents 1
- Lacks cytochrome P450 enzyme-inducing potential, explaining its minimal drug-drug interactions 5, 4
Functional Effects on Brain Activity
- In hippocampal recordings, levetiracetam inhibits burst firing without affecting normal neuronal excitability, suggesting selective action on pathological hyperexcitability 1
- Chronic treatment dose-dependently counteracts hippocampal hyperexcitability following status epilepticus, with complete restoration of normal parameters at 300 mg/kg/day 7
- The drug provides protection against secondarily generalized activity from focal seizures and displays inhibitory properties in kindling models 1
Clinical Implications of This Mechanism
- The SV2A mechanism provides broad-spectrum efficacy across partial-onset seizures, myoclonic seizures, and generalized tonic-clonic seizures 3, 5
- Unlike GABA-ergic drugs, levetiracetam has minimal impact on arousal function and does not cause cognitive impairment 2, 5
- Studies show no statistically significant worsening of arousal or sensory-perceptual functions at doses of 500-2000 mg/day, with some evidence of cognitive improvement 2
Important Caveats
- The precise molecular significance of SV2A binding remains incompletely understood, though experimental evidence strongly supports its role in the antiepileptic effect 1
- While levetiracetam may affect sensory-perceptual functions theoretically, clinical studies have not consistently demonstrated this effect 2
- The drug's unique mechanism means it works through pathways distinct from traditional antiepileptics, explaining why it remains effective in patients refractory to other agents 8, 9