The role of adenosine in epilepsy

Abstract

Adenosine is a well-characterized endogenous anticonvulsant and seizure terminator of the brain. Through a combination of adenosine receptor-dependent and -independent mechanisms, adenosine affects seizure generation (ictogenesis), as well as the development of epilepsy and its progression (epileptogenesis). Maladaptive changes in adenosine metabolism, in particular increased expression of the astroglial enzyme adenosine kinase (ADK), play a major role in epileptogenesis. Increased expression of ADK has dual roles in both reducing the inhibitory tone of adenosine in the brain, which consequently reduces the threshold for seizure generation, and also driving an increased flux of methyl-groups through the transmethylation pathway, thereby increasing global DNA methylation. Through these mechanisms, adenosine is uniquely positioned to link metabolism with epigenetic outcome. Therapeutic adenosine augmentation therefore not only holds promise for the suppression of seizures in epilepsy, but moreover the prevention of epilepsy and its progression overall. This review will focus on adenosine-related mechanisms implicated in ictogenesis and epileptogenesis and will discuss therapeutic opportunities and challenges.

Keywords: Adenosine kinase; DNA methylation; Disease modification; Epigenetics; Epileptogenesis; Seizures.

Figure 1.

A model of epileptic pathology progression with strategic therapeutic intervention points. As the disease state of epilepsy develops, maladaptive changes to ADK expression and adenosine tone build in series to a progressively more severe outcome. In this review, many therapeutic strategies are discussed; select opportunities for such interventions are shown at their appropriate time points here.

Figure 2.

The epigenetic role of adenosine: a comparison of the normal physiological (A) and epileptic(B) states in the transmethylation pathway. Due to clearance of adenosine by overexpression of ADK in the pathological state, the shifted equilibrium (indicated by the large red arrow) drives this pathway to hypermethylation, a hallmark of epileptogenesis.

Figure 3.

Adenosine flux between neurons and astrocytes in the brain. Astrocytes serve as a sink for synaptic levels of adenosine. Equilibrative nucleoside transporters (ENTs) normally equilibrate extra- and intracellular adenosine levels; however conditions of increased intracellular ADK drive the influx of adenosine into the cell yielding reduced extracellular levels of adenosine and – consequentially – reduced adenosine receptor activation; ATP, the major source of adenosine, can be released from neurons and astrocytes via vesicles or directly through hemichannels from astrocytes. Adenosine can then be generated through the activity of ectonucleotidases to complete the balance of the ATP / adenosine conversion cycle. The physiological functions of adenosine receptors are more extensively covered in other articles of this Special Issue; briefly, the interactions of select adenosine receptors and metabolite transporters are shown here. Presynaptically, A2A receptors antagonize the inhibitory effect of the A1 receptor on inhibiting calcium (Ca2+) import, which ultimately modulates vesicular release of ATP and glutamate. Postsynaptically, the A1 receptor inhibits calcium import of the N-methyl-D- aspartate receptor (NMDA), increases the conductance of potassium (K+), and inhibits adenylate cyclase (AC); A2A receptors have an opposing stimulation of dendritic AC. A2A receptors also play a role in vasodilation of blood vessels in the brain and periphery. Because the implications of the adenosine system in oligodendrocytes and microglia for epilepsy are largely unknown, those cell-types have been omitted to enhance clarity.

Figure 4.

Summary of key findings in adenosine augmentation methods. Many of the potential outcomes of adenosine augmentation are seen to overlap in ameliorating the symptoms and comorbidities associated with adenosine deficiency and epilepsy. As new therapeutic strategies emerge, it is useful to consider the interplay and novel effects of these different methods.