Abstract
Objective: Sudden unexpected death in epilepsy (SUDEP) is a fatal event that ranks second in years of potential life lost among neurological disorders. Seizure-induced respiratory arrest (S-IRA) is the primary instigator leading to death in many SUDEP cases. However, there are currently no effective preventive strategies against S-IRA other than the seizure control. Therefore, it is critical to develop new avenues to prevent SUDEP by investigating the pharmacological interventions of S-IRA. In the present study, we examined the effect of genistein, an isoflavone found in various dietary vegetables, on the incidence of S-IRA in DBA/1 mice.Methods: DBA/1 mice exhibited generalized seizures and S-IRA when subjected to acoustic stimulation. Genistein was intraperitoneally administered alone or in combination with an adrenoceptor antagonist and a serotonin (5-HT) receptor antagonist, respectively. The effects of drug treatments on S-IRA incidence and seizure behaviors were examined.Results: The incidence of S-IRA in DBA/1 mice was significantly reduced 2 h after injection of genistein at 1–90 mg/kg as compared with that in the vehicle control. Genistein could block S-IRA without interfering with any component of seizures, especially at relatively lower dosages. The S-IRA-suppressing effect of genistein was reversed by an α2 adrenoceptor antagonist but was not altered by an α1 antagonist. The inhibitory effect of genistein on S-IRA was not affected by a 5-HT3 or 5-HT2A receptor antagonist.Significance: Our data show that genistein reduces S-IRA incidence and can specifically block S-IRA in DBA/1 mice. Its suppressing effect on S-IRA is dependent on activating α2 adrenoceptors. Our study suggests that genistein, a dietary supplement, is potentially useful to prevent SUDEP in at-risk patients.
Highlights
Sudden unexpected death in epilepsy (SUDEP) ranks second in years of potential life lost among common neurological disorders [1]
Compared with that in the vehicle control, the incidence of seizure-induced respiratory arrest (S-IRA) was not significantly suppressed by genistein at 0.2 mg/kg (50%, n = 8) (Figure 1). Among those DBA/1 mice whose S-IRA was blocked by genistein, genistein at 1 mg/kg inhibited S-IRA without interfering with any component of audiogenic seizures in 100% of mice, suggesting that genistein blocks S-IRA in these mice
We report in this study that systemic administration of genistein, a compound found in many dietary vegetables and a dietary supplement widely available over the counter, lowers the incidence of S-IRA and blocks S-IRA in DBA/1 mice
Summary
Sudden unexpected death in epilepsy (SUDEP) ranks second in years of potential life lost among common neurological disorders [1]. Multiple pathophysiological mechanisms have been proposed for SUDEP [4,5,6,7,8,9]. Both clinical and animal studies demonstrated that seizure-induced respiratory arrest (S-IRA) is the major cause of death in SUDEP [10,11,12,13,14,15,16,17,18,19,20]. Investigating the pathophysiology and pharmacological interventions of S-IRA is of great significance to foster the development of new avenues to prevent SUDEP in patients
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