Galanin Analogs Prevent Seizure-Induced Respiratory Arrest

SUMMARY Objective Sudden Unexpected Death in Epilepsy (SUDEP) accounts for 20% of mortality in those with recurrent seizures. While risk factors, monitoring systems, and standard practices are in place, the pathophysiology of SUDEP is still not well understood. Better knowledge of SUDEP and its potential mechanisms of action is crucial to reducing risk in this patient population and developing potential treatment options. Clinical studies and animal models of SUDEP suggest that diminished post-ictal respiratory control may be the dominant mechanism contributing to mortality. Recently, it was demonstrated that the depletion of the neuropeptide galanin in the amygdala occurs in human SUDEP. The amygdala plays a key role in the central integration of respiratory signaling; the depletion of galanin may represent a critical change that predisposes individuals to SUDEP. Methods To evaluate the potential benefit of enhancing galaninergic signaling as a means to protect against SUDEP, we studied seizure-induced respiratory arrest (S-IRA) following central (intracerebroventricular, intra-amygdala) and systemic (intraperitoneal, subcutaneous) administration of galanin agonists. Seizure naïve and seizure experienced (fully kindled) mice were tested. Results Central and systemically-administered galanin analogs protect against S-IRA in naïve C57Bl/6J mice. Differential efficacy between receptor subtype-selective analogs varied based on the route of administration. Sub-chronic systemic administration at doses that reduced 6 Hz seizures also protected against S-IRA. Acute treatment benefits also extended to fully kindled mice subjected to tonic extension. Significance These data demonstrate that galanin agonists may be protective against post-ictal respiratory collapse. KEY POINTS Central and systemic galanin agonists prevent seizure-induced respiratory arrest. Efficacy was observed in three separate mouse strains under various experimental conditions. Sub-chronic administration demonstrated galanin agonist protection against respiratory arrest. Acute systemic administration also conferred protection against respiratory arrest following tonic extension. Galanin analogs may represent a novel potential therapy in SUDEP-susceptible individuals.