Abstracts

Rationale: During generalized seizures, adenosine is released, which is a known respiratory depressant (see Shen et al, 2010). Respiratory depression is observed in patients in association with generalized seizures (Bateman et al., 2008), which may contribute to sudden unexpected death in epilepsy (SUDEP) that occurs in human epileptics and in animal models of SUDEP, including DBA/1 and DBA/2 mice. GEPRs are a genetic model of generalized seizures that very rarely die after seizures. This study in GEPRs and DBA/2 mice evaluated the effects on respiration and the incidence of seizure-related death of administering (i.p.) drugs that prolong adenosine effects by blocking its metabolism [erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA), an adenosine deaminase inhibitor, and 5-iodotubericidin (ITU), an adenosine kinase inhibitor].Methods: DBA/2 mice (5-8 g, 21-23 days old) and GEPRs (250-400 g) were evaluated for susceptibility to audiogenic seizure-induced respiratory arrest (S-IRA), using an electrical bell (122 dB SPL). Animals that exhibited seizures but NOT S-IRA were used in subsequent experiments. The mice were treated with 5-iodotubericidin (ITU, 1 mg/kg) and GEPRs were treated with EHNA and ITU at doses of 10-30 and 1-3 mg/kg, respectively. Blood oxygen saturation (SpO₂%) was measured using a pulse oximetry sensor clipped to the animal s paw. Seizure was induced 30 min after drug administration to determine effects on respiration and incidence of death. Resuscitation was instituted, using a rodent respirator, if animals exhibited S-IRA. Results: Following seizures there was a decrease in percent SpO₂ in untreated GEPRs from 94.7% 0.58 (SEM) before seizure to 74.5 3.2%, which was significantly greater in the EHNA/ ITU group (30/3 mg/kg) to 53.0% 12.2% and 49.9% 15. There was also an increase in number of an auto-resuscitation reflex (respiratory gasps) to 7 2.0 in the EHNA and ITU group compared to controls (2.6 0.96). At 24 hr there were no significant differences between control and treated groups in these parameters. A significant incidence of death was also observed in the drug treated GEPRs (1-48 hr) after treatment, but no deaths occurred in untreated GEPRs. In DBA/2 mice that did not exhibit S-IRA initially there was a significant (80%) incidence of S-IRA 30 min after ITU treatment, which was successfully resuscitated. The mice returned to exhibiting seizure without S-IRA 24 hr after treatment. Conclusions: The present findings indicate that GEPRs may be able to model seizure-induced respiratory defects seen in patients after seizures, and this can lead to death if adenosine metabolism is blocked. These findings also indicate that respiratory depression, leading to S-IRA and death in both models, can be induced by blocking the breakdown of adenosine and suggest that preventative measures for SUDEP should explore the use of agents that reduce the effect of adenosine. (Support: EAM & SIUSM) Bateman et al., Brain 131 (Pt 12):3239-3245, 2008 Shen et al., Epilepsia.2010 Mar;51(3):465-8