Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) accounts for at least 20% mortality in patients with recurrent seizures. Despite the availability of several monitoring systems and standards of practice, there are currently no established therapies to prevent SUDEP. Thus, there is a need for novel treatments. Several clinical studies and animal models of SUDEP have suggested that diminished postictal respiratory control leading to hypoxia and/or apnea may be the dominant mechanism contributing to mortality. We have also learned that depletion of the neuropeptide galanin in the amygdala occurs in human SUDEP (Somani et al., Epilepsia. 2020 Feb;61(2):310-318.). The amygdala plays a crucial role in the central integration of respiratory signaling, and the chronic depletion of galanin over time may represent a critical change that predisposes individuals to SUDEP. The supplementation of galanin signaling through different administration pathways may suggest a novel therapeutic strategy to prevent SUDEP.

Methods: Using several mouse models, we evaluated the role of galanin agonists 810-2 and 505-5 in the prevention and protection of mortality following seizures. Treatment naïve (Sox-Cre/C57BI/6J), or corneal kindled (C57 B1/6J) mice, were treated with either vehicle (1% Tween 20, Phosphate-buffered saline), 810-2, or 505-5 by intraperitoneal (i.p.), intracerebroventricular (i.c.v.), or direct amygdala injections between 15 minutes to 1 hour before testing. Maximal electroshock seizures (150 mA, 0.2 sec, corneal stimulation) were used as a model of seizure-induced respiratory arrest. Following seizure induction, mice were observed for the presence of tonic extension and postictal breathing.

Results: Vehicle-treated mice all demonstrated tonic extension, which produced a lethal respiratory arrest. Both 810-2 and 505-5 did not protect animals against tonic extensions at any of the doses used. However, higher doses of both agonists, 810-2 (16mg/kg, i.p.) and 505-5 (4mg/kg i.p.) demonstrated significantly lower mortality rates than the vehicle. This may suggest that the enhancement of galanin signaling within respiratory neurocircuitry will prevent postictal respiratory collapse in animal models of SUDEP.

Conclusions: The following studies demonstrate that galanin may have protective properties against seizure-induced respiratory arrest and that the acute depletion of this neuropeptide is relevant to postictal amygdala dysfunction. Further studies with these analogs may further elucidate whether the galanin receptor subtype demonstrates a greater role in reducing seizure-induced respiratory arrest.

Funding: Please list any funding that was received in support of this abstract.: The ALSAM Foundations.