Inhibition of adenosine metabolism induces changes in post-ictal depression, respiration, and mortality in genetically epilepsy prone rats

A major cause of mortality in epilepsy patients is sudden unexpected death in epilepsy (SUDEP). Post-ictal respiratory dysfunction following generalized convulsive seizures is most commonly observed in witnessed cases of human SUDEP. DBA mouse models of SUDEP are induced by audiogenic seizures (AGSz) and show high incidences of seizure-induced death due to respiratory depression. The relatively low incidence of human SUDEP suggests that it may be useful to examine seizure-associated death in an AGSz model that rarely exhibits sudden death, such as genetically epilepsy-prone rats (GEPR-9s). Adenosine is released extensively during seizures and depresses respiration, which may contribute to seizure-induced death. The present study examined the effects of inhibiting adenosine metabolism on the durations of post-ictal depression (PID) and respiratory distress (RD), changes in blood oxygen saturation (% SpO2), and the incidence of post-seizure mortality in GEPR-9s. Systemic administration of adenosine metabolism inhibitors, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA, 30 mg/kg) with 5-Iodotubericidin (5-ITU, 3 mg/kg) in GEPR-9s resulted in significant changes in the duration of AGSz-induced PID as compared to vehicle in both genders. These agents also significantly increased the duration of post-seizure RD and significantly decreased the mean% SpO2 after AGSz, as compared to vehicle but only in females. Subsequently, we observed that the incidences of death in both genders 12-48 h post-seizure were significantly greater in drug vs. vehicle treatment. The incidence of death in females was also significantly higher than in males, which is consistent with the elevated seizure sensitivity of female GEPR-9s developmentally. These results support a potentially important role of elevated adenosine levels following generalized seizures in the increased incidence of death in GEPR-9s induced by adenosine metabolism inhibitors. These findings may also be relevant to human SUDEP, in light of the elevated adenosine levels that occur post-ictally in humans and its respiratory depressant actions.