Galanin Agonists as a Novel Neurotherapeutic Strategy for SUDEP
Abstract number :
232
Submission category :
1. Basic Mechanisms / 1F. Other
Year :
2020
Submission ID :
2422578
Source :
www.aesnet.org
Presentation date :
12/6/2020 12:00:00 PM
Published date :
Nov 21, 2020, 02:24 AM
Authors :
Cameron Metcalf, University of Utah;;
Rationale:
Sudden unexpected death in epilepsy (SUDEP) accounts for at least 20% of mortality in patients with recurrent seizures. While monitoring systems and standard practices are in place, to truly prevent SUDEP we need novel therapies with validated mechanisms of action. Clinical studies and animal models of SUDEP suggest that diminished post-ictal respiratory control may be the dominant mechanism contributing to mortality. Recently, we 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.). As the amygdala plays a key role in the central integration of respiratory signaling, depletion of galanin may represent a critical change that pre-disposes individuals to SUDEP. Further, supplementation of galanin signaling may represent a novel therapeutic strategy to prevent SUDEP.
Method:
Using a mouse model of seizure-induced respiratory arrest, we evaluated the role of the galanin agonist 810-2 in preventing mortality following seizures. Sox-Cre (C57Bl/6J mice) were treated with either vehicle (20% hydroxypropyl beta cyclodextrin, 3.75% mannitol, acetate buffer pH 3.5) or 810-2 (8 mg/kg and 16 mg/kg) by intraperitoneal injection one hour prior to 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 post-ictal breathing.
Results:
Vehicle-treated mice all demonstrated tonic extension, which produced a lethal respiratory arrest in 71% of mice (15/21). 810-2 did not protect animals against tonic extension at either dose tested. However, 810-2 at a dose of 16 mg/kg significantly reduced mortality 19% (3/16).
Conclusion:
Results from these studies demonstrate that galanin may protect against seizure-induced respiratory arrest. 810-2 is a galanin receptor 2 agonist and future studies may elucidate the role of galanin receptor subtypes in contributing to the role of galanin in protecting against respiratory arrest following seizures.
Funding:
:University of Utah, Department of Pharmacology & Toxicology
Basic Mechanisms