Physician Scientist Massachusetts General Hospital and Harvard Medical School
This abstract is recognized by Partners Against Mortality in Epilepsy for its contribution to improving the understanding of epilepsy-related mortality
Rationale: The incidence of sudden unexpected death in epilepsy (SUDEP) in patients with epilepsy is more than 20-fold higher than that of death in the general population. Previous studies in epileptic patients and animal models reveal that seizure-induced respiratory arrest (S-IRA) is the primary instigator of death in SUDEP. It has been demonstrated that enhancing serotonin (5-HT) function relieves S-IRA in animal models of SUDEP, including DBA/1 mice, and 5-HT3 receptors are involved in this S-IRA-suppressing effect of 5-HT enhancement. However, it remains unknown if other subtypes of 5-HT receptors contribute to S-IRA suppression. In the present study, we investigated the action of an agonist of the 5-HT1A, 5-HT2A, 5-HT2B and 5-HT2C receptor on S-IRA in DBA/1 mice. Methods: Naïve DBA/1 mice exhibit low incidence of S-IRA, but primed DBA/1 mice (subjected to daily acoustic stimulation at 96 dB SPL for three to four days) are consistently susceptible to S-IRA, which can be resuscitated using a rodent ventilator, allowing for multiple testing of S-IRA in the same mouse. The susceptibility of a primed DBA/1 mouse to S-IRA was confirmed 24 hours prior to the experiment. An agonist of the 5-HT1A (8-OH-DPAT), 5-HT2A (TCB-2), 5-HT2B (BW723C86) or 5-HT2C (MK-212) receptor, or vehicle was intraperitoneally (i.p.) administered 30 minutes prior to acoustic simulation, and the effect of each drug on the incidence of S-IRA was tested and digitally recorded for offline analysis. The incidence of S-IRA between drug treatment and vehicle control was compared using the Chi-square test. Results: The incidence of S-IRA was significantly reduced by TCB-2 at 10 mg/kg (30%, n = 10; p < 0.01) but was not altered by TCB-2 at 5 mg/kg (75%, n = 8) or 1 mg/kg (100%, n = 8) as compared with that of vehicle (saline) control (100%, n = 9) in DBA/1 mice. Compared with saline control, S-IRA was not altered by 8-OH-DPAT at 10 mg/kg (80%, n = 10), 5 mg/kg (77.8%, n = 9) or 1 mg/kg (88.9%, n = 9). The incidence of S-IRA was not changed by MK-212 at 20 mg/kg (100%, n = 9) or 10 mg/kg (100%, n = 8) as compared with saline control. BW723C86 did not affect S-IRA at 20 mg/kg (75%, n = 8), 10 mg/kg (100%, n = 8) or 2 mg/kg (100%, n = 8) as compared with vehicle (distilled water with 5% tween 80) control (87.5%, n = 8). Conclusions: 5-HT2A receptors are involved in S-IRA in DBA/1 mice. 5-HT1A, 5-HT2B and 5-HT2C receptors are unlikely to contribute to S-IRA. Funding: Please list any funding that was received in support of this abstract.: Supported by NIH R21NS101311, R01NS112319 and Departmental fund to HJF. ZT is a receipt of graduate fellowship from China Scholarship Council.