Abstracts

Anti-seizure medications (ASMs) are widely used to manage epilepsy and other neurological disorders by modulating neuronal excitability through different pathways. Some ASMs improve sleep quality by reducing seizure frequency and enhancing deep sleep, while others can disrupt normal sleep architecture, suppress REM sleep, or cause sedation and insomnia.

This study aimed to compare the effects of three widely used ASMs with different mechanisms of action - Diazepam, a benzodiazepine, acting as a positive allosteric modulator of GABA_A receptors, Cenobamate, enhancing inhibitory GABA_A receptor activity and inhibiting persistent sodium currents, and Valproate, which has a broad mechanism of action, including inhibition of voltage-gated sodium channels, increased GABA availability and modulation of T-type calcium channels. The effects of these three ASMs were evaluated on seizure and sleep architecture in murine models.

We assessed the anticonvulsant efficacy of these compounds using the 6 Hz psychomotor seizure test (32 and 44 mA stimulation) in Swiss mice and the audiogenic seizure test in DBA/2 mice. A separate cohort of mice was implanted with cortical and hippocampal electrodes to evaluate sleep-related effects. Telemetry EEG signals were analyzed following drug administration to evaluate alterations on sleep-wake architecture, i.e. REM and non-REM sleep and wake duration.

All three ASMs significantly reduced seizure incidence in both the 6 Hz and audiogenic seizure models, however, they also induced distinct changes in sleep architecture. Cenobamate and Diazepam prominently increased non-REM sleep while decreasing REM sleep during the initial 12-hour post-treatment period. Valproate exhibited a more moderate modulation of both REM and non-REM phases.

These findings highlight that while Cenobamate, Diazepam, and Valproate are effective in reducing seizure activity, they also modify sleep architecture. The differential impact on REM and non-REM sleep underscores the importance of considering sleep-related outcomes when evaluating ASM efficacy. Integrating sleep assessments into preclinical studies can therefore provide a more comprehensive understanding of the effects of ASMs.