Galanin analogs prevent mortality from seizure-induced respiratory arrest in mice

Abstract

ObjectiveSudden 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.Materials and methodsTo evaluate the impact of enhancing galaninergic signaling to potentially protect against SUDEP, we studied seizure-induced respiratory arrest (S-IRA) following central (intracerebroventricular, intra-amygdala) and systemic (intraperitoneal, subcutaneous) administration of galanin analogs. Seizure naïve and seizure experienced (fully kindled) mice were tested.ResultsCentral 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 experiencing tonic extension.SignificanceThese data demonstrate that galanin analogs may be protective against post-ictal respiratory collapse.

Diet composition and sterilization modifies intestinal microbiome diversity and burden of Theiler’s virus infection-induced acute seizures

“…PTZ assay can be substantially altered by acute TMEV infection history, but that this seizure threshold test can evoke significant mortality in C57BL/6J mice. 17 C57BL/6J mice are generally more susceptible to mortality following a generalized tonic clonic seizure, 54 thus we sought to use a less severe seizure model to pair to the chronic behavioral testing at 6 weeks after TMEV infection. The minimal clonic test is also known to reveal reduced seizure susceptibility following a TMEV infection.…”

Sex and gonadectomy modify behavioral seizure susceptibility and mortality in a repeated low‐dose kainic acid systemic injection paradigm in mice

“…As a result, using this RLDKA protocol to study post‐SE sequelae in ORX males will likely require protocol modifications, such as reduced doses or increased intervals between injections. Conversely, the increased rate of mortality in ORX C57BL/6J males may suggest that a comparison of testis‐intact and ORX males in this RLDKA paradigm may be useful in identifying mechanisms associated with sudden unexpected death in epilepsy 67,68 …”

Sudden unexpected death in epilepsy

“…These represent attractive avenues for investigating pharmacological reduction of SUDEP risk. Very recent work in mice indicates that analogues of the neuropeptide, galanin, can prevent seizure-induced respiratory arrest and death in kindled mice [130], which may occur through action in the amygdala [131].…”