Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is one of the most common causes of death in people with epilepsy. It is generally considered to result from seizure-related cardiac dysfunction, respiratory depression, autonomic nervous dysfunction, or brain dysfunction. SUDEP occurs with greater prevalence in males than in females, despite there being no clear gender differences in the incidence and prevalence of generalized epilepsy.

In the mouse, hormonal fluctuations in females may affect seizure susceptibility and for this reason males are typically used given that SUDEP incidence may be more stable in this gender.

The aim of our experiment was to evaluate if there was a detectable difference in the susceptibility of male and female DBA/1 mice in a SUPED model and to compare the effects of two well-known serotonergic modulators, Fenfluramine and Fluoxetine.


Methods: After weaning, DBA/1 mice were submitted to sound stimulation once daily over 3 days and the presence of respiratory arrests following tonico-clonic convulsions was evaluated. The mice showing at least one respiratory arrest on the third priming day or 2 - 3 respiratory arrests over the 3 priming days were included in the experiments.


Results: Batch to batch variation in the percent of respiratory arrest is observed in both males and females on Days 1 and 2 of priming, but reaches a maximal effect on Day 3 with most of animals exhibiting respiratory arrest (approx. 90%).

On testing day, respiratory arrest was observed in all tested male and female mice confirming the susceptibility of DBA/1 mice to respiratory arrest following audiogenic seizure.

Fenfluramine inhibited tonic-clonic convulsions and thus protected against respiratory arrest in both genders. Fluoxetine at the doses tested reduced the number of respiratory arrests while tonic-clonic convulsions were still observed in the male and female DBA/1 mouse indicating no sex differences.


Conclusions: These results show that almost all DBA/1 mice exhibit respiratory arrest after 3 days of priming and confirm the beneficial effects of serotoninergic modulators such as Fenfluramine and Fluoxetine in both genders. These data highlight that the use of male and female mice can be more translational and predictive in a SUDEP model for evaluating the potency of new drug candidates to decrease seizure-induced respiratory arrest incidence.


Funding: N/A