Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is a devastating epileptic event. Several pathophysiological mechanisms including respiratory/cardiac depression have been proposed to contribute to SUDEP. DBA/1 mice are a good animal model of SUDEP, as they exhibit respiratory arrest (RA) leading to sudden death after generalized seizures. DBA/1 mice can be resuscitated using a rodent ventilator within 2-5 s after RA occurs (Faingold and Randall, 2013). Studies also indicate that cardiac functional changes occur secondarily to RA in DBA mice, suggesting that RA may play a causative role in this SUDEP model. Thus, we hypothesize that respiratory stimulants can be used as a pharmacological approach to preventing RA in DBA/1 mice. PK-THPP is a potent TASK-3 antagonist, and systemic administration of PK-THPP substantially enhances respiratory ventilation in rats (Cotten, 2013). However, its effect on breathing in DBA/1 mice remains unclear. In the current study, we investigated for the first time the effect of systemic administration of PK-THPP on ventilation and RA in DBA/1 mice. Methods: Adult DBA/1 mice were anesthetized using 1.5% isoflurane in room air, and non-invasive plethysmography was used to quantify spontaneous respiratory function in the absence and presence of PK-THPP. PK-THPP was dissolved in a solvent with 4% DMSO and 10% cremophor. The minute ventilation (MV) after injection of the solvent or PK-THPP or application of 7% CO₂ was normalized to the corresponding baseline. The effect of PK-THPP on RA was tested in unanesthetized DBA/1 mice. RA was confirmed 24 hr prior to drug treatment. Audiogenic seizures and RA were induced using an electric bell (96 dB SPL) 15 min after administration of PK-THPP. RA and the pattern/duration of audiogenic seizures were recorded on videotapes for offline analysis. Results: After injection of PK-THPP (10 mg/kg, i.p.), the minute ventilation (MV) of DBA/1 mice gradually increased within 5 min and reached peak at ~15 min. The normalized peak MV evoked by PK-THPP was significantly greater than that of solvent (173.8 ± 7.7% vs. 91.0 ± 5.3%; n = 3; p<0.001). Moreover, PK-THPP also increased the sensitivity to hypercapnia in DBA/1 mice. Pre-treatment with PK-THPP significantly increased the normalized MV in response to CO