Activation of central 5HT2A receptor in brain inhibited the seizure-induced respiratory arrest in the DBA/1 mouse SUDEP model

Sudden unexpected death in epilepsy (SUDEP) is the fatal cause leading to the death of epilepsy patients with anti-epileptic drug resistance. However, the underlying mechanism of SUDEP remains to be elusive. Our previous study demonstrated that enhancement of serotonin (5-HT) synthesis by intraperitoneal (IP) injection of 5-hydroxytryptophan in brain significantly reduced the incidence of seizure-induced respiratory arrest (S-IRA) in DBA/1 mice SUDEP models. Given that 5HT2A receptor (5HT2AR) acts an important role in mediating respiration system in brain, we hypothesized that 5HT2AR is of great significance to modulate S-IRA and SUDEP. To test this hypothesis, we examined whether the decreased incidence S-IRA evoked by either acoustic stimulation or PTZ by blocking 5HT2AR by administration with ketanserin (KET), a selective antagonist of 5HT2AR, in DBA/1 mice SUDEP models to test the role of 5HT2AR modulating S-IRA. Our results suggested that the decreased incidence of S-IRA by 5-Hydroxytryptophan (5-HTP), a precursor for central nervous system (CNS) serotonin (5-HT) synthesis, was significantly reversed by IP and intracerebroventricularly (ICV) injection of ketanserin in our models. Thus, our data suggested that 5-HT2AR in the brain may be a potential and specific target to prevent SUDEP.