Adenosine has two faces: Regionally dichotomous adenosine tone in a model of epilepsy with comorbid sleep disorders

Warren, Ted J.; Simeone, Timothy A.; Smith, David; Grove, Ryan; Adamec, Jiřı́; Samson, Kaeli; Roundtree, Harrison M.; Madhavan, Deepak; Simeone, Kristina A.

doi:10.1016/j.nbd.2018.01.017

Cited by 10 publications

(8 citation statements)

References 51 publications

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“…It is hypothesized that a decreased adenosine tone uniformly forms the base for both epilepsy and sleep disruption (90). However, recent study found a lineal association of regionally distinguishable dichotomous levels of adenosine in one model represent both epilepsy and comorbid sleep disorders (110). In the model, adenosine level was decreased in the dorsal hippocampus contributing to seizure threshold diminution, while adenosine level was increased in the lateral hypothalamus leading to chronic partial sleep deprivation.…”

Section: Adenosine Dysfunction In Comorbidities Associated With Epilepsymentioning

confidence: 99%

Role of DNA Methylation and Adenosine in Ketogenic Diet for Pharmacoresistant Epilepsy: Focus on Epileptogenesis and Associated Comorbidities

Fan

Luan

et al. 2019

Front. Neurol.

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Epilepsy is a neurological disorder characterized by a long term propensity to produce unprovoked seizures and by the associated comorbidities including neurological, cognitive, psychiatric, and impairment the quality of life. Despite the clinic availability of several novel antiepileptic drugs (AEDs) with different mechanisms of action, more than one-third of patients with epilepsy suffer with pharmacoresistant epilepsy. Until now, no AEDs have been proven to confer the efficacy in alteration of disease progression or inhibition of the development of epilepsy. The ketogenic diet, the high-fat, low-carbohydrate composition is an alternative metabolic therapy for epilepsy, especially for children with drug-resistant epilepsy. Recently clinical and experimental results demonstrate its efficacy in ameliorating both seizures and comorbidities associated with epilepsy, such as cognitive/psychiatric concerns for the patients with refractory epilepsy. Of importance, ketogenic diet demonstrates to be a promising disease-modifying or partial antiepileptogenesis therapy for epilepsy. The mechanisms of action of ketogenic diet in epilepsy have been revealed recently, such as epigenetic mechanism for increase the adenosine level in the brain and inhibition of DNA methylation. In the present review, we will focus on the mechanisms of ketogenic diet therapies underlying adenosine system in the prevention of epileptogenesis and disease modification. In addition, we will review the role of ketogenic diet therapy in comorbidities associated epilepsy and the underlying mechanisms of adenosine.

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Section: Adenosine Dysfunction In Comorbidities Associated With Epilepsymentioning

confidence: 99%

Role of DNA Methylation and Adenosine in Ketogenic Diet for Pharmacoresistant Epilepsy: Focus on Epileptogenesis and Associated Comorbidities

Fan

Luan

et al. 2019

Front. Neurol.

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“…Adenosine levels increase during wakefulness and are depleted during sleep (163, 168). The sleep disturbances often associated with epilepsy may be explained by alterations in adenosine signaling (169). Adenosine is an endogenous anticonvulsant and adenosine levels increase during seizures (170, 171).…”

Section: Potential Mechanismsmentioning

confidence: 99%

“…Furthermore, manipulations to adenosine or its clearance modulate epileptogenesis (171–173). Having recurrent seizures may, in turn, decrease, or increase adenosine levels in different brain areas (169). Adenosine analogs applied to the brainstem of rats cause prolonged suppression of breathing (174, 175).…”

Section: Potential Mechanismsmentioning

confidence: 99%

Dead in the Night: Sleep-Wake and Time-Of-Day Influences on Sudden Unexpected Death in Epilepsy

2018

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Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death in patients with refractory epilepsy. Convergent lines of evidence suggest that SUDEP occurs due to seizure induced perturbation of respiratory, cardiac, and electrocerebral function as well as potential predisposing factors. It is consistently observed that SUDEP happens more during the night and the early hours of the morning. The aim of this review is to discuss evidence from patient cases, clinical studies, and animal research which is pertinent to the nocturnality of SUDEP. There are a number of factors which might contribute to the nighttime predilection of SUDEP. These factors fall into four categories: influences of (1) being unwitnessed, (2) lying prone in bed, (3) sleep-wake state, and (4) circadian rhythms. During the night, seizures are more likely to be unwitnessed; therefore, it is less likely that another person would be able to administer a lifesaving intervention. Patients are more likely to be prone on a bed following a nocturnal seizure. Being prone in the accouterments of a bed during the postictal period might impair breathing and increase SUDEP risk. Sleep typically happens at night and seizures which emerge from sleep might be more dangerous. Lastly, there are circadian changes to physiology during the night which might facilitate SUDEP. These possible explanations for the nocturnality of SUDEP are not mutually exclusive. The increased rate of SUDEP during the night is likely multifactorial involving both situational factors, such as being without a witness and prone, and physiological changes due to the influence of sleep and circadian rhythms. Understanding the causal elements in the nocturnality of SUDEP may be critical to the development of effective preventive countermeasures.

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“…Excessive increases in extracellular adenosine suppress neuronal activity and may contribute to PGES and the postictal state (Rosen and Berman, 1985;During and Spencer, 1992). Though acute seizures cause an increase in extracellular adenosine, chronic epilepsy is associated with a reduction of baseline adenosine levels, which could be a precipitating factor in epileptogenesis (Gouder et al, 2004;Li et al, 2008) and associated co-morbid conditions including cognitive, psychiatric, and sleep disorders (Yee et al, 2007;Boison et al, 2012;Shen et al, 2012;Boison, 2016;Warren et al, 2018). Spreading depolarization waves, which can occur during seizures, result in a prolonged increase in extracellular adenosine Abbreviations: 5-ITU, 5-iodotubercidin; A 1/2A , adenosine receptor; ADK, adenosine kinase; ATP, adenosine triphosphate; DPCPX, A 1 receptor antagonist; dnSNARE, N-ethylmaleimide-sensitive factor attachment protein receptor; EEG, electroencephalogram; EKG, electrocardiogram; EHNA, erythro-9-(2-hydroxy-3-nonyl)-adenine hydrochloride; GEPR-9s, genetically epilepsy-prone rats; GRAB Ado , GPCR-activation based adenosine sensor; PGES, postictal generalized EEG suppression; SCH 442416, A 2A receptor antagonist; SUDEP, sudden unexpected death in epilepsy.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Adenosine has two faces: Regionally dichotomous adenosine tone in a model of epilepsy with comorbid sleep disorders

Cited by 10 publications

References 51 publications

Role of DNA Methylation and Adenosine in Ketogenic Diet for Pharmacoresistant Epilepsy: Focus on Epileptogenesis and Associated Comorbidities

Role of DNA Methylation and Adenosine in Ketogenic Diet for Pharmacoresistant Epilepsy: Focus on Epileptogenesis and Associated Comorbidities

Dead in the Night: Sleep-Wake and Time-Of-Day Influences on Sudden Unexpected Death in Epilepsy

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

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