Deficiency of Norepinephrine Transmission In Brain Contributed To Seizure-Induced Respiratory Arrest And Is Implicated in ADHD with SUDEP In DBA/1 mice

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 to date. Although we had previously reported that seizure-induced respiratory arrest (S-IRA) plays an important role in modulating the occurrence of SUDEP, the exact mechanism of it to decode still needs to be explored. Given that our previous findings suggested that S-IRA evoked by acoustic stimulation or pentylenetetrazole (PTZ) was markedly reduced by systemic administration of atomoxetine, a selective norepinephrine reuptake inhibitor (NRI), in DBA/1mice SUDEP model and norepinephrine α-1 receptor (NEα-1R) in brain acts as an important player in mediating the respiration function , we hypothesized that the suppressed effects of S-IRA by atomoxetine was via acting on NEα-1R. To test this hypothesis, we examined whether the suppressant incidence S-IRA evoked by either acoustic stimulation or PTZ by atomoxetine in DBA/1 mice SUDEP model . Our results suggest that the decreased incidence of S-IRA by atomoxetine was significantly reversed by intraperitoneal (IP) and intracerebroventricularly (ICV) injection of prazosin, a selective antagonist of NEα-1R in our models. Furthermore, no obvious changes of electroencephalogram (EEG) data in cerebral cortex between the group with administration with atomoxetine and the group with administration of prazosin in PTZ injection SUDEP model to be observed. Thus, our data suggest that deficiency of norepinephrine transmission contributed to seizure-induced respiratory arrest and NEα-1R in the brain may be a potential and specific target to prevent SUDEP. Keywords: SUDEP, prazosin, norepinephrine, norepinephrine α-1receptor, generalized seizures, heart rate, blood pressures