A novel mouse model for sudden unexpected death in epilepsy (SUDEP): Role of impaired adenosine clearance

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Shen HY, Li T, and Boison D (2009) A novel mouse model for sudden unexpected death in epilepsy (SUDEP): Role of impaired adenosine clearance.

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Abstract: 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.

Keywords: adenosine; adenosine clearance; SUDEP; kainic acid; seizure; caffeine

Context

  • Valuable mouse-model study of possible role of adenosine in SUDEP. Kainate-induced seizures in the presence of increased levels of adenosine by inhibition of adenosine-inactivating enzymes led to rapid death. Administration of caffeine, an antagonist of the adenoisne receptor, prolonged survival after seizure onset. The article cites earlier work analyzing microdialysate from epilepsy patients found to be high in adenosine after seizures as evidence that adenosine is released during seizures as an endogenous anticonvulant. Important validations of this model would be verification that adenosine levels are increased in or immediately after seizure in patients (the short half-life of adenosine could complicate this study) and determination of the dose of the caffeine level that would be needed in humans. One caveat is the clinical report of two cases in which caffeine appeared to precipitate seizures Singh et al.

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