Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) accounts for up to 17% of deaths in patients with epilepsy, ranking second in public health burden among common neurological disorders. Both clinical and animal studies show that seizure-induced respiratory arrest (S-IRA) is the primary cause of death in SUDEP. Our previous study demonstrated that atomoxetine, a norepinephrine reuptake inhibitor (NRI), suppresses S-IRA in DBA/1 mice, suggesting that noradrenergic neurotransmission is involved in S-IRA. However, it remains unknown which adrenergic receptors contribute to S-IRA suppression. In the current study, we systemically administered adrenergic agonists and antagonists and determined the adrenergic receptors that play important roles in modulating S-IRA.  Methods: DBA/1 mice were primed by daily exposure to acoustic stimulation (96 dB SPL) for 3-4 days starting from postnatal day 26-28 until they became consistently susceptible to S-IRA, which could be resuscitated using a rodent ventilator. S-IRA was confirmed 24 hr prior to experiments. Atomoxetine (an NRI), clonidine (an adrenergic alpha2 receptor agonist), cirazoline (an alpha1 receptor agonist), yohimbine (an alpha2 receptor antagonist), prazosin (an alpha1 receptor antagonist) or vehicle (saline) was intraperitoneally (i.p.) administered alone or in combination, and the effects of drug treatments on the incidence of S-IRA was examined and digitally recorded for offline analysis. Chi-square test was used to compare the incidence of S-IRA between drug treatment and saline control.  Results: The incidence of S-IRA in primed DBA/1 mice was significantly reduced 30 min after i.p. administration of clonidine, an alpha2 receptor agonist, at 0.1 mg/kg (37.5%, n = 8; p < 0.01), 0.5 mg/kg (10%, n = 10; p < 0.001), 2 mg/kg (0%, n = 8; p < 0.001) and 8 mg/kg (11.1%, n = 9; p < 0.001) as compared with that of vehicle control (100%, n = 10). Compared with vehicle control, S-IRA was not altered 30 min after i.p. injection of cirazoline, an alpha1 receptor agonist, at 0.04-1 mg/kg. As reported previously, S-IRA was reduced 2 hr after i.p. administration of atomoxetine at 20 mg/kg (12.5%, n = 8); interestingly, administration of 5 mg/kg yohimbine, an alpha2 receptor antagonist, 30 min prior to atomoxetine injection significantly reversed the suppressing effect of atomoxetine on S-IRA (90%, n = 10) (p < 0.01). However, administration of 1 mg/kg prazosin, an alpha1 receptor antagonist, 30 min prior to atomoxetine injection did not significantly reversed the suppressing effect of atomoxetine on S-IRA.  Conclusions: Adrenergic alpha2 receptors play an important role in modulating S-IRA in DBA/1 mice.  Funding: Supported by NIH R21NS101311 and Departmental fund to HJF. RZ is a receipt of postdoctoral fellowship, and ZT is a receipt of graduate fellowship from China Scholarship Council.