Levetiracetam's Mechanism: Neurotransmitter Modulation
Levetiracetam (Keppra) does not "block" a specific neurotransmitter release in the traditional sense; rather, it modulates presynaptic neurotransmitter release through binding to synaptic vesicle protein 2A (SV2A), with activity-dependent effects on both excitatory (glutamate) and inhibitory (GABA) transmission. 1, 2
Primary Mechanism of Action
Levetiracetam binds to synaptic vesicle protein 2A (SV2A), representing a novel class of anticonvulsant action distinct from traditional mechanisms like sodium channel blockade or GABA enhancement. 1, 2
The drug modulates presynaptic neurotransmitter release in a use-dependent and frequency-dependent manner, meaning it primarily affects neurons during high-frequency firing patterns typical of seizure activity. 3
Effects on Neurotransmitter Release
Glutamate (Excitatory) Effects
Levetiracetam reduces excitatory neurotransmitter release during trains of high-frequency activity, with the largest effect on later responses in high-frequency trains. 3
The drug decreases glutamate release in epileptic conditions, helping to restore the pathologically elevated glutamate/GABA ratio back toward normal levels. 4
GABA (Inhibitory) Effects
Paradoxically, levetiracetam also reduces inhibitory GABA transmission in a frequency-dependent manner, though this occurs at lower concentrations and with shorter latency than its effects on excitatory transmission. 5
However, under epileptic conditions with high potassium stimulation, levetiracetam preferentially increases vesicular GABA release, which may contribute to its antiseizure efficacy. 4
In animal models of excitotoxicity, levetiracetam prevents the QUIN-induced decrease in GABA release while simultaneously preventing the increase in glutamate release. 6
Clinical Relevance of the Mechanism
The SV2A binding mechanism provides broad-spectrum efficacy across partial-onset seizures, myoclonic seizures, and generalized tonic-clonic seizures. 1
Unlike GABA-ergic drugs (such as benzodiazepines), levetiracetam has minimal impact on arousal function and does not cause cognitive impairment at therapeutic doses of 500-2000 mg/day. 1, 2
Important Mechanistic Nuances
The drug requires vesicular uptake through endocytosis to access its SV2A binding site, which explains why prolonged exposure (3 hours in research models) is needed before effects become apparent. 3
Levetiracetam's effects are activity-dependent, meaning it preferentially affects neurons that are firing at high frequencies, which provides selectivity for pathological hyperexcitability while sparing normal neurotransmission. 5, 3
The net effect in epileptic tissue is restoration of the excitatory/inhibitory balance by reducing the pathologically elevated glutamate/GABA ratio. 4