Vanillin suppresses seizure-induced mortality in the DBA/1 mouse model of SUDEP

Sudden unexpected death in epilepsy (SUDEP) poses a significant public health burden. Seizure-induced apnea has been identified as a major event leading to death after generalized seizures. Vanillin, an herbal compound, stimulates monoaminergic signaling. Given that enhancing the function of monoamines [serotonin (5-HT) and norepinephrine (NE)] reduces seizure-induced mortality in animal models of SUDEP, we hypothesized that vanillin prevents seizure-induced mortality in DBA/1 mice. DBA/1 mice of both sexes were primed by acoustic stimulation once daily for 3-4 days. Vanillin, ondansetron (a 5-HT₃ receptor antagonist), ketanserin (a 5-HT_2A antagonist), GR 125487 (a 5-HT₄ antagonist), yohimbine (a α2 adrenoceptor antagonist), prazosin (a α1 antagonist), ICI 118,551 (a β2 antagonist), SB 366791 (a TRPV1 antagonist) or vehicle was administered intraperitoneally 30-60 min before acoustic stimulation, and the effects of each drug or drug combination (an antagonist + vanillin) on seizure-induced mortality, apnea or seizures were examined. The incidence of seizure-induced mortality was significantly reduced by vanillin at 300 and 400 mg/kg as compared with the vehicle control. Vanillin treatment was associated with reduced seizure-induced apnea and blockade of tonic seizures. Notably, the reduction in seizure-induced mortality by vanillin was not reversed by antagonists of monoaminergic receptors, despite their reported involvement in seizure-induced deaths, nor by an antagonist of TRPV1 receptors, a known direct target of vanillin. These findings demonstrate that vanillin suppresses seizure-induced mortality in DBA/1 mice, with associated effects on respiratory dysfunction and tonic seizures, and suggest that this protection is unlikely to be mediated by monoaminergic or TRPV1 pathways.