Biology subjects

Duyvesteyn, E.

Publications and source records attributed to Duyvesteyn, E..

2 recordsLinked to original sources

bioRxiv2022

Breathing dysfunction and alveolar damage in a mouse model of Dravet syndrome

ObjectiveThe incidence of Sudden Unexpected Death in Epilepsy (SUDEP) is especially high in those with Dravet syndrome (DS). Risk factors have been identified, but the mechanism(s) by which death occurs is not fully understood. Evidence supports ventilatory dysfunction in the pathophysiology of SUDEP. Understanding specific respiratory patterns present at baseline and after seizures at different ages, as well as the health of lung tissue, will allow us to better understand how sudden death occurs in this population. MethodsWhole body plethysmography (WBP) was used to monitor respiration before and after electrically induced seizure in the Scn1aA1783V/WT mouse model of DS weekly for a period of four weeks. Following the four-week WBP study, lungs from surviving animals were collected and stained with hematoxylin and eosin and Weigerts elastin and the density of tissue and elastin were analyzed. ResultsBreathing was diminished in the DS mouse at baseline and following evoked seizures in younger aged mice (P18-P24), consistent with prolonged post-ictal inspiratory time and low respiratory drive compared to the response seen in older animals. In older DS mice, consisting of those that have survived a critical period for mortality, the response to seizure was more robust and included higher respiratory drive, peak inspiratory and expiratory flow rates, tidal and expiratory volumes, and breathing frequency compared to wild-type and relative to baseline. Alveolar damage was also observed in P46-P52 DS mice. SignificanceDifferences in specific respiratory parameters in younger DS animals, during the time when mortality is greatest, compared to older DS animals (i.e. those that have survived the critical period) may allow us to better understand respiratory differences contributing to SUDEP. Lung tissue damage in DS may also contribute to respiratory dysfunction in SUDEP. KEY POINTSO_LIBaseline respiration is diminished in DS mice compared to wild type. C_LIO_LIElectrically induced seizure produced a different respiratory response in younger DS mouse compared to older DS animals. C_LIO_LIAlveolar septal damage is present in DS mice. C_LIO_LIBaseline and post-ictal breathing dysfunction and inefficient oxygenation and CO2 clearance likely potentiated by lung damage may serve as a potential mechanism by which SUDEP occurs in DS. C_LI

physiology↗

bioRxiv2022

Galanin Analogs Prevent Seizure-Induced Respiratory Arrest

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. MethodsTo 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 naive and seizure experienced (fully kindled) mice were tested. ResultsCentral and systemically-administered galanin analogs protect against S-IRA in naive 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. SignificanceThese data demonstrate that galanin agonists may be protective against post-ictal respiratory collapse. KEY POINTSO_LICentral and systemic galanin agonists prevent seizure-induced respiratory arrest. C_LIO_LIEfficacy was observed in three separate mouse strains under various experimental conditions. C_LIO_LISub-chronic administration demonstrated galanin agonist protection against respiratory arrest. C_LIO_LIAcute systemic administration also conferred protection against respiratory arrest following tonic extension. C_LIO_LIGalanin analogs may represent a novel potential therapy in SUDEP-susceptible individuals. C_LI

neuroscience↗