Rationale: Cenobamate is a novel antiseizure medication (ASM) approved for the treatment of focal seizures in adults. In phase 2 trials, cenobamate has demonstrated a robust antiseizure effect in patients with difficult-to-treat focal seizures, including focal aware motor, focal impaired awareness, and focal to bilateral tonic-clonic. Cenobamate is currently being studied in primarily generalized tonic-clonic seizures. Cenobamate’s mechanism of action (MOA) is unique and bi-modal, combining selective blockade of persistent sodium currents (I
NaP) and positive allosteric γ-aminobutyric acid type A (GABA
A) receptor modulation.
Methods: We review the available evidence and provide further insight related to cenobamate’s MOA.
Results: Preclinical studies showed that cenobamate exerts effects on voltage-gated sodium channels (Na
V) and GABA
A receptors. The I
NaP contributes to the generation of a paroxysmal depolarization shift, which may serve as a basis for epileptic foci. There is an increase in I
NaP in spontaneously bursting hippocampal neurons after epileptogenic stimuli such as experimental status epilepticus. In preclinical studies, cenobamate modulated Na
V by preferential blockade of the I
NaP, while sparing the transient sodium current (I
NaT). It is likely that by sparing the
I
NaT, cenobamate does not interfere with fast-spiking GABAergic interneuron function, thus preserving network inhibition. The effect of cenobamate’s selective
I
NaP block on the resting membrane potential is augmented by its positive allosteric modulation of GABA
A receptor- mediated tonic currents. This enhances the I
NaT, presumably via preferential potentiation of the tonic (extrasynaptic) receptors. This potentiation was not reversed by flumazenil and cenobamate did not displace flunitrazepam binding, which suggests positive allosteric GABA
A modulation via non-benzodiazepine binding sites. The combined effects of limiting the
I
NaP while augmenting the I
NaT effectively suppresses the epileptiform activity of principal neurons. Cenobamate’s selectivity for the I
NaP over the I
NaT likely represents action on the Na
V1.6 channel over the Na
V1.1 channel and is a feature not shared by traditional ASMs like phenytoin or carbamazepine.
Conclusions: Cenobamate selectively inhibits the I
NaP, while sparing the I
NaT. Cenobamate’s selective inhibition of the I
NaP may involve preferential action at Na
V1.6 over Na
V1.1 channels. Sparing of the I
NaT is critical for preserving the inhibitory activity of fast-spiking interneurons. This effect may be enhanced by cenobamate’s positive allosteric modulation of tonic (extrasynaptic) GABA
A receptors.
Funding: Funded by SK Life Science, Inc.