Abstracts

SUDEP is devastating for epileptic patients and their families but has been difficult to model in animals, which has been a barrier to developing therapeutic interventions. The basis of SUDEP in patients may involve convulsion-induced respiratory failure. We propose that SUDEP can be modeled by the DBA/2 mouse. There is a high incidence of convulsion-induced death in DBA/2 mice, which can be prevented by prompt respiratory support. Major components of the respiratory neuronal network of mammals is known to reside in the brainstem, and this network is modulated by several neurotransmitters, including serotonin (5HT). The present study examined whether agents that affect 5HT neurotransmission can affect the susceptibility of DBA/2 mice to SUDEP. DBA/2 mice (24 day old) were initially screened for susceptibility to audiogenic seizures (AGS) and SUDEP by exposing them to an electrical bell (122 dB SPL) until the onset of tonus for a maximum duration of 60 sec. Attempts to revive animals that exhibited SUDEP involved placement of a nasal tube connected to a rodent respirator (180 strokes/min). The surviving mice were subsequently placed into two groups: the SUDEP group exhibited respiratory arrest, while the non-SUDEP group experienced AGS but maintained respiration. The SUDEP mice were given the 5HT uptake inhibitor, fluoxetine (fluox, ip), and the non-SUDEP mice were given the 5HT antagonist, cyproheptadine (cypro, ip), 24 hr after the initial AGS. Of 145 DBA/2 mice tested, 73% exhibited SUDEP, and in our most recent study, most of these mice (94%) could be revived using respiratory support. The DBA/2 mice in the recent study exhibited SUDEP (76%, of 46 mice), while the remainder (N=11), were in the non-SUDEP group. Fluox (10 mg/kg) in SUDEP-expressing DBA/2 mice resulted in block of SUDEP in 100% of animals (N=9), and the mice returned to SUDEP susceptibility (89%, N= 9) 72 hr later. The incidence of tonic hind limb extension (THE) was significantly reduced by fluox concomitantly. Cypro (1 mg/kg) in non-SUDEP DBA/2 mice resulted in respiratory arrest in 83% (N= 6) of mice that exhibited THE, and it could be reversed with respiratory support. Most (90%) non-SUDEP DBA/2 mice that did not exhibit THE (N=10) also did not exhibit respiratory arrest. These data indicate that the DBA/2 mouse model of SUDEP exhibits respiratory-mediated death but can be revived by respiratory support. SUDEP in DBA/2 mice is modulated by agents that alter 5HT neurotransmission, which suggests that agents which enhance the effect of 5HT might be useful in SUDEP prevention, while agents that block 5HT action should be avoided in epileptic patients that might be subject to SUDEP. Respiratory cessation in DBA/2 mice is also closely associated with expression of THE in this SUDEP model. (Supported by CURE, Christopher Donalty Memorial Award)