The Good, the Bad, and the Deadly: Adenosinergic Mechanisms Underlying Sudden Unexpected Death in Epilepsy

Adenosine is an inhibitory modulator of neuronal excitability. Neuronal activity results in increased adenosine release, thereby constraining excessive excitation. The exceptionally high neuronal activity of a seizure results in a surge in extracellular adenosine to concentrations many-fold higher than would be observed under normal conditions. In this review, we discuss the multifarious effects of adenosine signaling in the context of epilepsy, with emphasis on sudden unexpected death in epilepsy (SUDEP). We describe and categorize the beneficial, detrimental, and potentially deadly aspects of adenosine signaling. The good or beneficial characteristics of adenosine signaling in the context of seizures include: (1) its direct effect on seizure termination and the prevention of status epilepticus; (2) the vasodilatory effect of adenosine, potentially counteracting postictal vasoconstriction; (3) its neuroprotective effects under hypoxic conditions; and (4) its disease modifying antiepileptogenic effect. The bad or detrimental effects of adenosine signaling include: (1) its capacity to suppress breathing and contribute to peri-ictal respiratory dysfunction; (2) its contribution to postictal generalized EEG suppression (PGES); (3) the prolonged increase in extracellular adenosine following spreading depolarization waves may contribute to postictal neuronal dysfunction; (4) the excitatory effects of A_2A receptor activation is thought to exacerbate seizures in some instances; and (5) its potential contributions to sleep alterations in epilepsy. Finally, the adverse effects of adenosine signaling may potentiate a deadly outcome in the form of SUDEP by suppressing breathing and arousal in the postictal period. Evidence from animal models suggests that excessive postictal adenosine signaling contributes to the pathophysiology of SUDEP. The goal of this review is to discuss the beneficial, harmful, and potentially deadly roles that adenosine plays in the context of epilepsy and to identify crucial gaps in knowledge where further investigation is necessary. By better understanding adenosine dynamics, we may gain insights into the treatment of epilepsy and the prevention of SUDEP.