Abstract
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 A2A 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.
Highlights
The purine ribonucleoside adenosine is found ubiquitously in living tissues
In the forebrain, seizureinduced adenosine surging has the beneficial effect of stopping seizures; excessive adenosine signaling may potentiate sudden unexpected death in epilepsy (SUDEP) through respiratory suppression, postictal generalized EEG suppression (PGES) exacerbation, and attenuation of the hypercapnic ventilatory response (Shen et al, 2010; Ashraf et al, 2020)
We summarize the evidence pertinent to the adenosine hypothesis of SUDEP and describe the multifarious effects of adenosine signaling in the context of epilepsy: the good, the bad, and the deadly
Summary
The purine ribonucleoside adenosine is found ubiquitously in living tissues. In the central nervous system, adenosine is an essential inhibitory modulator of neuronal excitability (Dunwiddie, 1980; Dunwiddie and Masino, 2001; Boison, 2008). Deficits in adenosine signaling can facilitate status epilepticus, a life-threatening event defined by inordinately protracted seizure activity (Young and Dragunow, 1994; Kochanek et al, 2006) In this sense, seizure-induced adenosine surging is highly beneficial. Seizure-induced increases in brainstem adenosine levels may make seizures more dangerous by preventing an adequate respiratory response to postictal blood gas derangement For these reasons, seizure-induced adenosine surging is “bad” for patient health. In the forebrain, seizureinduced adenosine surging has the beneficial effect of stopping seizures; excessive adenosine signaling may potentiate SUDEP through respiratory suppression, PGES exacerbation, and attenuation of the hypercapnic ventilatory response (Shen et al, 2010; Ashraf et al, 2020). We summarize the evidence pertinent to the adenosine hypothesis of SUDEP and describe the multifarious effects of adenosine signaling in the context of epilepsy: the good, the bad, and the deadly
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
