Abstracts

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with drug-resistant epilepsy. Due to the unpredictable and largely unwitnessed nature of SUDEP, its pathophysiological mechanisms remain poorly understand however recent work has highlighted the role of ictal and postictal central apnea, which precedes bradycardia and subsequent cardiac arrest. Therefore, understanding the neural mechanisms underlying ictal and postictal respiratory dysfunction and exploring pharmacological interventions to ameliorate these deficits may aid in the development of preventative therapeutics. Recent preclinical studies have shown that targeting orexin receptors may correct progressive cardiorespiratory deficits in a genetic model of epilepsy. More specifically, orexin receptor antagonism (with a dual orexin receptor antagonist or DORA) improves sleep impairments, bradycardia, and ventilatory responses in a Kv1.1 KO mouse line, a genetic model which exhibits spontaneous seizures and high mortality. This work clearly demonstrates that the orexin system may be targeted to improve interictal cardiac and respiratory function, however it’s critical to investigate the efficacy of orexinergic modulation on peri-ictal respiratory dysfunction.

Here, we utilize the DBA/1 mouse line which has audiogenic seizures (AGSs) or seizures that are triggered by a loud, broad tone. In fact, these mice exhibit full tonic-clonic seizures which are often fatal due to seizure-induced respiratory arrest and cardiac arrest, unless mechanically ventilated with a mouse resuscitator, making them a commonly used SUDEP model. To examine the effects of targeting orexin receptors on postictal respiration, mice were pretreated systemically with either a DORA or an orexin-1 receptor (OX1R) agonist or their respective vehicles. 30 minutes post-injection, AGSs were induced, mice were resuscitated and then put into whole-body plethysmography (WBP) chambers for continuous, noninvasive monitoring of respiration. Following a 30-minute baseline, the mice were exposed to 7% CO2 for 15 minutes to examine the hypercapnic ventilatory response (HCVR), and this was followed by a 15-minute washout period. Baseline, gas phase, and washout phase tidal volume (TV), respiratory frequency (RF), and minute ventilation (MV) were compared across treatment groups.

Supported by other literature, AGSs robustly blunted baseline respiration and the HCVR. Interestingly, DORA pretreatment further blunted postictal HCVR while OX1R agonism partially corrected the blunted HCVR. Specifically, DORA pretreatment further reduced gas phase TV and MV but the OX1R agonist increased gas phase TV, in comparison with vehicle treated mice.

These data suggest that, while orexin receptor antagonism may improve interictal cardiorespiratory function, it may worsen postictal ventilation. Future work must explore the effects of orexin receptor modulation on both interictal and postictal respiration in DBA/1 mice across repeated AGSs to determine if these mice respond differently after many seizures, perhaps evidencing adaptations in the orexin system.