Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is the key cause resulting in the death of epilepsy patients. The underlying mechanism of SUDEP seems to be elusive. Although our previous studies demonstrated that seizure-induced respiratory arrest (S-IRA) plays an important role in the occurrence of SUDEP, the exact mechanism seems still to be explored. Given that norepinephrine plays a key role in modulating respiration and our previous findings that S-IRA evoked by acoustic stimulation or pentylenetetrazole (PTZ) was markedly reduced by atomoxetine, a selective norepinephrine reuptake inhibitor, in DBA/1mice, which showed S-IRA evoked by acoustic stimulation and pentylenetetrazole (PTZ) was markedly reduced by atomoxetine, we hypothesized that the suppressed effects of S-IRA by atomoxetine was via acting on norepinephrine α-1 receptor ( NEα-1R). To test this hypothesis, we examined the S-IRA evoked by either acoustic stimulation or pentylenetetrazole in DBA/1 mice SUDEP model. Our results suggest that the incidence of S-IRA was significantly revered by administration with prazosin, a selective antagonist of NEα-1R. Our data suggest that NEα-1R in the brain may be a potential target to prevent SUDEP. Methods: Seizure-induced respiratory arrest (S-IRA) of DBA/1 mice evoked by acoustic stimulation using an electrical bell (96 dB SPL) without interval for 60 seconds once daily for 3-4 days starting at postnatal day 26-28 (primed DBA/1 mice) to evoke the occurrence of until the occurrence of generalized tonic-clonic seizures (GTCS). Meanwhile, S-IRA also was established after generalized tonic-clonic seizures evoked by PTZ (75mg/kg, i.p.), as described previously (Zhang et al., Epilepsia,2016;57(8):1228-1235, Zhang et al., Epilepsy Behav. 2017 ;73:6-9, Zhang et al.,Neurobiol Dis. 2018;110:47-58). Aimed at acoustic stimulation method, S-IRA was always confirmed 24 hr prior to experiment. Control group: Atomoxetine or vehicle (saline) was administered i.p. 2 hr before acoustic stimulation; Experimental group: Atomoxetine was administered i.p. 2 hr before acoustic stimulation and prazosin was administered i.p. 30 mins before acoustic stimulation.and the effect of atomoxetine and prazosin (vehicle) on S-IRA was examined and digitally recorded for offline analysis, respectively. Additionally, Prazosin was administered the selective antagonist of NEα-1R prazosin intracerebroventricularly (ICV) in DBA/1 mice in different groups. Results: Compared with vehicle group in primed DBA/1 mice(n=6), the rate of S-IRA evoked by acoustic stimulation was significantly reduced by atomoxetine with the doseage of 15 mg/kg ,i.p ( p < 0.05, n=6). The lower rate of S-IRA by atomoxetine was markedly prazosin i.p ( p < 0.01,n=6). From the another SUDEP model established by PTZ, Compared with vehicle control (n = 6), the rate of S-IRA evoked by PTZ was significantly reduced by atomoxetine with the doseage of 15 mg/kg ,i.p ( p < 0.05, n=6and the lower rate was significantly reversed by prazosin ICV. The seizure score of two models from different groups was no significantly difference ( p >