Cenobamate

The approved antiepileptic Cenobamate has shown great potential as a novel neuroprotective drug for the treatment of central nervous system (CNS) injuries. Cenobamate functions in two neuroprotective ways: 1) a strong inhibitor of persistent voltage-gated Na+ channels (INaP), which prevents neuronal depolarization and glutamate release and 2) a positive allosteric modulator of GABAA receptors, which increases tonic inhibition and hyperpolarizes neurons.
These actions can counteract the secondary injury cascade, a feedback loop of Na+ influx, Ca2+ overload, mitochondrial dysfunction, and excitotoxicity that occurs after a traumatic or stroke-induced injury. Compared to traditional antiepileptic drugs, the ability of Cenobamate to inhibit INaP makes it a more effective agent against excitotoxicity. The GABAaR modulating activity also leads to activation of the PI3K/Akt-CREB-BDNF pathway, inducing anti-apoptotic factors and repressing pro-apoptotic factors. In preclinical TBI models, Cenobamate has been observed to reduce infarct volume and improve memory function after injury without increasing the incidence of side effects. Other desirable attributes include a rapid onset and a long half-life. Synergizes with riluzole-like Na+ channel inhibition.

Fig. 1 The potential mechanism of Cenobamate. (Wiciński M.; et al. 2021)