A novel mouse model for sudden unexpected death in epilepsy (SUDEP): role of impaired adenosine clearance.
Sudden unexpected death in epilepsy (SUDEP) is a significant cause of mortality in people with epilepsy. Two postulated causes for SUDEP, cardiac and respiratory depression, can both be explained by overstimulation of adenosine receptors. We hypothesized that SUDEP is a consequence of a surge in adenosine as a result of prolonged seizures combined with deficient adenosine clearance; consequently, blockade of adenosine receptors should prevent SUDEP. Here we induced impaired adenosine clearance in adult mice by pharmacologic inhibition of the adenosine-removing enzymes, adenosine kinase and deaminase. Combination of impaired adenosine clearance with kainic acid-induced seizures triggered sudden death in all animals. Most importantly, the adenosine receptor antagonist caffeine, when given after seizure onset, increased survival from 23.75 +/- 1.35 min to 54.86 +/- 6.59 min (p < 0.01). Our data indicate that SUDEP is due to overactivation of adenosine receptors and that caffeine treatment after seizure onset might be beneficial.
Shen
Hai-Ying
HY
Robert Stone Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, USA.
Li
Tianfu
T
Boison
Detlev
D
D000225:Adenine / Q000031:analogs & derivatives; D000241:Adenosine / Q000378:metabolism*; D058892:Adenosine Deaminase Inhibitors; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002423:Cause of Death; D003645:Death, Sudden / Q000209:etiology* / Q000517:prevention & control; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000401:mortality* / Q000503:physiopathology; D007608:Kainic Acid; D051379:Mice; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D012307:Risk Factors; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology* / Q000517:prevention & control; D016019:Survival Analysis; D014372:Tubercidin / Q000031:analogs & derivatives / Q000494:pharmacology
D058892:Adenosine Deaminase Inhibitors; D004791:Enzyme Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; C034214:5-iodotubercidin; D002110:Caffeine; C010192:9-(2-hydroxy-3-nonyl)adenine; D000248:Adenosine Kinase; D000225:Adenine; D000241:Adenosine; D014372:Tubercidin; D007608:Kainic Acid