Effect of monoamine reuptake inhibition and α₁ blockade on respiratory arrest and death following electroshock‐induced seizures in mice

Abstract

Summary Objective Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. Although the mechanisms for SUDEP are incompletely understood, seizure‐induced respiratory arrest (S‐IRA) has been strongly and consistently implicated. A body of evidence indicates that serotonin (5‐HT), a modulator of breathing, plays a critical role in SUDEP. Because the 5‐HT and norepinephrine (NE) systems interact in many biologic processes and NE is known to modulate breathing and seizures, we hypothesized that NE may play a role in S‐IRA and SUDEP. Methods We examined the effects of pharmacologic manipulation of 5‐HT and NE on S‐IRA and death following maximal electroshock (MES)–induced seizures in adult wild‐type (WT) mice, genetically 5‐HT neuron–deficient (Lmx1bf/f/p) mice, and chemically NE neuron–deficient mice. Mice were treated with pharmacologic agents targeting the serotonergic and noradrenergic systems and subjected to seizure induction via MES while breathing was measured via whole‐body plethysmography. Results S‐IRA and death was reduced in WT mice with NE reuptake inhibitors (NRIs), reboxetine and atomoxetine, selective serotonin reuptake inhibitors (SSRIs), fluoxetine and citalopram, and the dual 5‐HT/NE reuptake inhibitor (SNRI), duloxetine. S‐IRA and death was also reduced in Lmx1bf/f/p mice with reboxetine and fluoxetine. The protective effects of the reuptake inhibitors were prevented by the α1 antagonist, prazosin. Citalopram did not reduce S‐IRA and death in NE neuron–deficient mice. Significance These data suggest that 5‐HT and NE critically interact in the modulation of breathing following a seizure and potentially inform preventive strategies for SUDEP.

The effect of time‐of‐day and circadian phase on vulnerability to seizure‐induced death in two mouse models

“…This result may indicate that vulnerability to seizure-induced death is not directly related to motor seizure severity. This may appear paradoxical; however, previous investigations have demonstrated that mortality and seizure severity are not necessarily correlated in the MES model (Buchanan et al 2014;Kruse et al 2019). Circadian rhythms did not alter apnoea related parameters in the animals that survived.…”

The effect of duloxetine on ECoG activity of absence-epilepsy model in WAG/Rij rats

“…[7] Recently a study reported that seizure-induced respiratory arrest and death was decreased in WT mice with duloxetine treatment in maximal electroshock-induced seizures in adult in mice. [17] Citraro et al (2015) demonstrated that chronic treatment of duloxetine (10 and 30 mg/kg) decreased both number and duration of SWDs in adult WAG/Rij rats. [6] In this study, both of the number and duration of SWDs parameters were significantly decreased in 5, 10 and 30 mg/kg duloxetine treatment groups compared to control.…”

Post-ictal generalized EEG suppression and seizure-induced mortality are reduced by enhancing dorsal raphe serotonergic neurotransmission

“…To determine whether stimulation of DRN neurons with acidosis could also reduce mortality, DRN neurons were stimulated with acidified aCSF for 10 min prior to seizure induction via MES, a model with known mortality (Buchanan, et al, 2014;Hajek and Buchanan, 2016;Kruse et al, 2019;Li and Buchanan, 2019;Purnell, et al, 2017). Perfusion of acidified aCSF into the DRN prior to MES induced seizures reduced mortality (4 survived vs 2 died; acidosis: n = 6; normal: n = 6; p < 0.05; Fig.…”