The adenosine hypothesis of SUDEP
[Part 2: Questions; Boison D & Shen H-Y]
Adenosine is a natural compound found in all parts of the human body. It is a key regulator of brain function (Boison, 2013a; Boison et al., 2013; Diógenes et al., 2014). In general, a seizure or brain injury causes excessive energy consumption and a consequent surge in adenosine (Clark, 1997; During, 1992) to conserve energy (Boison, 2013b) and limit the extent of injury (Fedele et al., 2006). In epilepsy, enhanced adenosine activity works as a self-protection mechanism to stop seizures by reducing neuronal activity at the seizure origin (Lado & Moshe, 2008). However, enhanced adenosine activity if in the brainstem, which is the brain region that controls heart and respiratory functions, may trigger apnea and cardiac arrest (Barraco et al., 1990; Evans et al., 1982; Herlenius et al., 1997). Thus, excessive adenosine after a seizure needs to be cleared to avoid cardiorespiratory depression. In the adult brain, adenosine clearance is mainly controlled by astrocytes through an adenosine removing enzyme, adenosine kinase (ADK). ADK in astrocytes maintains the homeostasis of adenosine in the brain (Boison, 2012; Boison, 2013b; Boison et al., 2010; Etherington et al., 2009). The ‘adenosine hypothesis of SUDEP’ predicts that a seizure-induced adenosine surge when combined with a deficit in metabolic adenosine clearance can trigger lethal apnea and/or cardiac arrest; and blocking of the adenosine function (e.g., using the adenosine blocker caffeine or theophylline) may prevent SUDEP.
The following evidence supports the adenosine hypothesis of SUDEP:
Clinical relevance of adenosine signaling in SUDEP: A study from the Cleveland Clinic showed that only 20% of 301 participants (all candidates for epilepsy surgery) did not use caffeine, whereas 80% drank caffeine up to 100 ounces or more per day (Source: Epilepsy.com). It is thus fair to predict that a substantial proportion of patients with epilepsy regularly consume rather high amounts of caffeine and related methylxanthines. Despite this, the use of dietary factors has received little attention in the study of SUDEP. While the chronic use of methylxanthines may increase seizure risk (Boison, 2010), the same stimulants may also reduce the risk for SUDEP. Importantly, SUDEP occurs predominantly at night and during sleep (Nobili et al., 2011; Lamberts et al., 2013), a time when plasma caffeine levels are lowest and brain adenosine levels are highest (Kim et al., 2012; Porkka-Heiskanen & Kalinchuk, 2011).
The role of adenosine in sudden infant death syndrome (SIDS): SIDS occurs in seemingly healthy babies characterized by respiratory arrest also seen in SUDEP, and may share a similar etiology with SUDEP (Hirsch et al., 2011; Tao et al., 2010). A SIDS-like condition in mice has been induced by the genetic deletion of ADK (Adk-/- mice) (Boison et al., 2002). 35% of all ADK-deficient pups died within the first four days after birth while in most cases their sudden death was accompanied by lethal apnea (Boison et al., 2002), which links the impairment of the metabolic clearance of adenosine with SIDS.
Caffeine prevents lethal apnea after traumatic brain injury (TBI): Like seizures, TBI also triggers an adenosine surge and severe TBI in patients leads to high CSF levels of adenosine associated with lethal apnea (Clark et al., 1997). A rat study evaluated whether lethal apnea after TBI is due to excessive activation of adenosine receptors in the brain stem and tested the potential preventive effect of caffeine. Rats with severe TBI showed prolonged periods of apnea and a mortality rate of 47% with a correlation between the duration of apnea and lethal outcome (Lusardi et al., 2012). Importantly, administering caffeine within one minute after the TBI prevented the extended apnea (as seen in untreated animals) and completely prevented lethal outcome (Lusardi et al., 2012) demonstrating that lethal apnea is preventable by reducing adenosine activity.
Deficiency in adenosine clearance triggers lethal outcome after seizures: A further study suggests that seizures may be lethal if there is a deficit in metabolic adenosine clearance. Mice pretreated with saline developed convulsive seizures after injection of kainic acid (KA), with no lethal consequences. In contrast, mice pretreated with adenosine clearance inhibitors prior to KA injection showed a delayed onset of seizures, presumably due to pharmacologically enhanced levels of the anticonvulsant adenosine. However, once seizures developed, all animals developed convulsive seizures and died (Shen et al, 2010), suggesting that a seizure-induced adenosine surge combined with deficient adenosine clearance might be a cause for SUDEP.
Caffeine enhances survival time after seizures: This study also tested whether adenosine receptor blockade can delay or prevent lethal outcome (Shen et al, 2010). Mice with KA-induced seizures received treatment of caffeine or saline 30 seconds after the onset of convulsive seizures. Caffeine treatment significantly prolonged survival time after seizure onset compared to saline treatment (Shen et al, 2010). This demonstrates that caffeine, when given after seizure onset, promotes survival.
Chronic recurrent seizures cause adaptive changes in adenosine metabolism in brainstem: The role of adenosine homeostasis was further evaluated in studies using an intra-hippocampal KA model of temporal lobe epilepsy (Gouder et al., 2003; Gouder et al., 2004). Epileptic mice developed hippocampal sclerosis and up-regulation of ADK in the brainstem. This might be an adaptive response to enhance metabolic adenosine clearance in a critical brain area. Thus, impairment of metabolic adenosine clearance in the brainstem might increase the risk for SUDEP.
SUDEP modeled in genetic mutant (Adk+/-) mice: To investigate whether impaired clearance of adenosine could contribute to SUDEP we injected KA to induce seizures in Adk+/- mice, which express only 50% of ADK (Boison et al., 2002). EEG recordings showed that epilepsy severity was reduced by half in the Adk+/- mice as compared to wild-type littermates of normal adenosine clearance. However, Adk+/- mice displayed an increased incidence of ‘sudden death’ while none of the wild-type littermates died during the same time span, hence supporting that impaired adenosine clearance might contribute to SUDEP.
Conclusions: Commonly used drugs, such as caffeine or theophylline, or agents used clinically to affect adenosine signaling or homeostasis might be repurposed for the possible prevention of SUDEP. However, the therapeutic use of caffeine may be a double-edged sword due to its widespread effect of both exacerbating seizures via blockade of the ‘anticonvulsant’ subtype of A1 adenosine receptors (Boison, 2010), and possibly preventing SUDEP by blocking adenosine receptors in the brain stem. The goal to maximize the anti-SUDEP effect of caffeine and to avoid any proconvulsant effects can be achieved by the use of region-selective and/or receptor subtype-selective therapies and the timing of therapy administration. With more research into the underlying mechanisms of SUDEP there is hope that therapeutic agents that are already available might be efficacious in the prevention of SUDEP. Furthermore, adenosine homeostasis in the brain is influenced by lifestyle factors such as diet, sleep, and exercise (Boison et al., 2013) and the potential role of such lifestyle choices as modifiers to SUDEP risk still needs to be evaluated.
Acknowledgments: DB is supported through grants from the NINDS (NS061844, NS065957), the US Department of the Army (W81XWH-12-1-0283) and Citizens United for Research in Epilepsy (CURE). HYS is supported through a SUDEP research grant from the Legacy Hospital Foundations.
Boison D, Chair & Director, Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, USA
Shen H-Y, Senior Research Associate, Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, USA
Reviewed Apr 2018; Original Dec 2014
How to cite:
Boison D & Shen H-Y. The adenosine hypothesis of SUDEP. In: Panelli R, Hanna J, Jeffs T, Brockett P, editors. Continuing the global conversation [online]. SUDEP Action & SUDEP Aware; 2018 [retrieved day/month/year]. Available from: www.sudepglobalconversation.com.