Adenosinergic signaling in epilepsy

Abstract

Despite the introduction of at least 20 new antiepileptic drugs (AEDs) into clinical practice over the past decades, about one third of all epilepsies remain refractory to conventional forms of treatment. In addition, currently used AEDs have been developed to suppress neuronal hyperexcitability, but not necessarily to address pathogenic mechanisms involved in epilepsy development or progression (epileptogenesis). For those reasons endogenous seizure control mechanisms of the brain may provide alternative therapeutic opportunities. Adenosine is a well characterized endogenous anticonvulsant and seizure terminator of the brain. Several lines of evidence suggest that endogenous adenosine-mediated seizure control mechanisms fail in chronic epilepsy, whereas therapeutic adenosine augmentation effectively prevents epileptic seizures, even those that are refractory to conventional AEDs. New findings demonstrate that dysregulation of adenosinergic mechanisms are intricately involved in the development of epilepsy and its comorbidities, whereas adenosine-associated epigenetic mechanisms may play a role in epileptogenesis. The first goal of this review is to discuss how maladaptive changes of adenosinergic mechanisms contribute to the expression of seizures (ictogenesis) and the development of epilepsy (epileptogenesis) by focusing on pharmacological (adenosine receptor dependent) and biochemical (adenosine receptor independent) mechanisms as well as on enzymatic and transport based mechanisms that control the availability (homeostasis) of adenosine. The second goal of this review is to highlight innovative adenosine-based opportunities for therapeutic intervention aimed at reconstructing normal adenosine function and signaling for improved seizure control in chronic epilepsy. New findings suggest that transient adenosine augmentation can have lasting epigenetic effects with disease modifying and antiepileptogenic outcome.

Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

“…Adenosine has been considered the main endogenous antiepileptic molecule, via the activation of presynaptic inhibitory A 1 receptors, and it has been proposed that augmentation of adenosine levels could be a solution to resolve drug-refractory epilepsies [48][49][50]. Our study suggests that this must be taken carefully since increased extracellular levels of adenosine may Fig.…”

“…Astrocytes influence the pathogenesis and pathophysiology of epilepsy by creating an excitatory feedback loop via the release of gliotransmitters, such as glutamate, D-serine, and ATP, and/ or by acting upstream on the homeostatic control of uptake, degradation, and recycling of neurotransmitters and neuromodulators, including adenosine (reviewed in [48]). In addition to their local modulatory role to exacerbate or synchronize neuronal firing on shorter timescales of milliseconds to minutes, long-lasting volume and morphological changes (e.g., perisynaptic branches swelling, extension, or retraction of processes) of reactive astrocytes may transform these cells into aberrant synaptic network integrators due to inhibition of neurotransmitter clearance, defective potassium buffering capacity, altered Ca 2+ signal propagation, and uncoupling of gap junction-mediated cell communication (reviewed in [54]).…”

“…Both processes are tightly linked to disruption of adenosine homeostasis and astroglial dysfunction ultimately leading to hippocampal sclerosis that is a characteristic pathological hallmark of MTLE (reviewed in [48]). The acute or initiating phase (lasting 2-3 h) is characterized by an acute surge in adenosine associated with a transient downregulation of astrocytic adenosine kinase (ADK), which commands the cellular uptake of the nucleoside from the extracellular milieu.…”

Overexpression of Adenosine Kinase in Patients with Epilepsy Associated With Sturge-Weber Syndrome

“…Because ADK activity is the principal factor controlling adenosine metabolism in the brain, minor changes in ADK activity translate rapidly into major changes in adenosine [30]. Dysregulation of ADK plays a significant role in the processes that turn a normal brain into an epileptic brain [14]. Experimental researches demonstrate that overexpression of ADK per se might be sufficient to trigger electrographic seizures [8,15,18,19,22].…”

“…Epileptic seizures and cognitive impairment are prominent clinical features of SWS and recent data suggest that the dysregulation of adenosinergic mechanism is involved in the development of epilepsy and its comorbidities [13,14]. Adenosine is an endogenous purine nucleoside that modulates a wide range of physiologic functions.…”