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

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.

Chronobiology of epilepsy and sudden unexpected death in epilepsy

“…Diurnal humans and nocturnal rodents share similar oscillations in adenosine ( Cornelissen et al, 1985 ; Chagoya de Sanchez et al, 1993 ; Chagoya de Sanchez, 1995 ; Huston et al, 1996 ), norepinephrine ( Linsell et al, 1985 ; Agren et al, 1986 ), serotonin ( Agren et al, 1986 ; Rao et al, 1994 ; Mateos et al, 2009 ), and melatonin ( Ralph et al, 1971 ; Lewy and Newsome, 1983 ). The role of adenosine and serotonin are of particular interest in SUDEP pathophysiology ( Massey et al, 2014 ; Petrucci et al, 2020 ; Purnell et al, 2021a ). Both adenosine and serotonin have been shown to have anticonvulsant effects ( Boison, 2006 ; Buchanan et al, 2014 ) and regulate breathing in response to alterations in blood gases ( Koos and Doany, 1991 ; Hodges et al, 2008 ; Hodges and Richerson, 2010 ; Koos, 2011 ; Iceman et al, 2013 ).…”

The role of sleep state and time of day in modulating breathing in epilepsy: implications for sudden unexpected death in epilepsy

“…The inhibitory neuromodulator, adenosine, is released in large quantities during seizures (During and Spencer, 1992 ; Berman et al, 2000 ; Van Gompel et al, 2014 ). This is likely a mechanism of seizure termination (Shen et al, 2010 ; Purnell et al, 2021a ). Unlike, 5-HT, NE, and orexin, adenosine promotes sleep and suppresses wakefulness (Feldberg and Sherwood, 1954 ; Buday et al, 1961 ; Haulicǎ et al, 1973 ; Huber et al, 2004 ).…”

“…This hypothesis posits that a surge of adenosine is released during a seizure as a termination mechanism. However, this large increase in extracellular adenosine can result in suppression of breathing which can lead to terminal respiratory failure (Shen et al, 2010;Purnell et al, 2021a). This is far from a comprehensive list of salient signaling molecules when it comes to respiratory function and SUDEP.…”

Understanding the Role of Glia-Neuron Communication in the Pathophysiology of Epilepsy: A Review

“…Since the level of extracellular adenosine mainly depends on ADK, any change in ADK expression can limit the adenosine level, reducing its anticonvulsant and neuroprotective functions. ADK dysfunction has been found in both animal and human epileptic models, and strong overexpression of ADK was observed in reactive astrocytes, indicating that adenosine deficiency is at least a contributing factor to seizure generation [75]. Even in the absence of astrogliosis, or any other epileptic event, ADK overexpression is sufficient to cause epileptic seizures [74].…”