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Review
. 2008 Mar;84(3):249-62.
doi: 10.1016/j.pneurobio.2007.12.002. Epub 2007 Dec 23.

The adenosine kinase hypothesis of epileptogenesis

Detlev Boison  1
Affiliations
Review

The adenosine kinase hypothesis of epileptogenesis

Detlev Boison. Prog Neurobiol. 2008 Mar.

Abstract

Current therapies for epilepsy are largely symptomatic and do not affect the underlying mechanisms of disease progression, i.e. epileptogenesis. Given the large percentage of pharmacoresistant chronic epilepsies, novel approaches are needed to understand and modify the underlying pathogenetic mechanisms. Although different types of brain injury (e.g. status epilepticus, traumatic brain injury, stroke) can trigger epileptogenesis, astrogliosis appears to be a homotypic response and hallmark of epilepsy. Indeed, recent findings indicate that epilepsy might be a disease of astrocyte dysfunction. This review focuses on the inhibitory neuromodulator and endogenous anticonvulsant adenosine, which is largely regulated by astrocytes and its key metabolic enzyme adenosine kinase (ADK). Recent findings support the "ADK hypothesis of epileptogenesis": (i) Mouse models of epileptogenesis suggest a sequence of events leading from initial downregulation of ADK and elevation of ambient adenosine as an acute protective response, to changes in astrocytic adenosine receptor expression, to astrocyte proliferation and hypertrophy (i.e. astrogliosis), to consequential overexpression of ADK, reduced adenosine and - finally - to spontaneous focal seizure activity restricted to regions of astrogliotic overexpression of ADK. (ii) Transgenic mice overexpressing ADK display increased sensitivity to brain injury and seizures. (iii) Inhibition of ADK prevents seizures in a mouse model of pharmacoresistant epilepsy. (iv) Intrahippocampal implants of stem cells engineered to lack ADK prevent epileptogenesis. Thus, ADK emerges both as a diagnostic marker to predict, as well as a prime therapeutic target to prevent, epileptogenesis.

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Figures

Fig. 1
Fig. 1
Components of the astrocyte-based adenosine cycle. Under physiological conditions a major source of synaptic adenosine is vesicular release of ATP (orange circle) from astrocytes followed by its extracellular degradation to adenosine (ADO) by a cascade of ectonucleotidase (EN). Under conditions of high-frequency stimulations neurons contribute to synaptic ATP release. Extra- and intracellular levels of adenosine are rapidly equilibrated, mainly by equilibrative nucleoside transporters (ent). Thus, synaptic concentrations of adenosine are largely dependent on its intracellular metabolism as the driving force for the influx of adenosine into the cell. Intracellular metabolism of adenosine (ADO) is depends on the activity of the astrocytic enzyme adenosine kinase (ADK), which, together with 5’-nucleotidase (5’-NT), forms a substrate cycle between AMP and adenosine. This substrate cycle is directly linked to the energy pool of the brain involving ADP and ATP. Under conditions of astrogliosis, ADK is overexpressed leading to an increased influx of adenosine into the astrocyte and therefore to reduced levels of synaptic adenosine favoring the development of spontaneous seizures. Conversely, inhibition of ADK or inhibition of nucleoside transporters can be used to increase synaptic adenosine and thus to suppress seizures.
Fig. 2
Fig. 2
The adenosine kinase hypothesis of epileptogenesis. Downregulation of adenosine kinase (ADK) within 2 to 3 hours results as a homotypic response to various types of brain injury including status epilepticus and stroke. Reduced ADK leads to an increase of extracellular adenosine (see Fig. 1). Under conditions of elevated adenosine, astrocytic A1Rs are downregulated, whereas upregulation of astrocytic A2ARs occurs. Since astrocyte proliferation is in part dependent on the relative expression levels of A1Rs (inhibition of cell proliferation) and A2ARs (promotion of cell proliferation), the adenosine-induced shift of the A1/A2A-equilibrium may cause astrogliosis. Astrogliosis in turn leads to upregulation of ADK, and thus results in a decrease of the endogenous anticonvulsant adenosine: spontaneous recurrent seizures result. Potential therapeutic effects of adenosine-releasing stem cell derived brain implants are shown in green. Focal augmentation of adenosine by these implants may prevent epileptogenesis based on the potent neuroprotective and anticonvulsant properties of adenosine.
Fig. 3
Fig. 3
Astrogliosis and upregulation of ADK in epilepsy. Left panel: Confocal image taken from untreated mouse (control) hippocampus showing the fine processes of a single astrocyte stained for GFAP immunoreactivity in green. ADK immunoreactivity in red shows a predominant location of ADK in the nucleus and cell body of this astrocyte. Right panel: In contrast, the epileptic mouse hippocampus, when analyzed three weeks after status epilepticus, is characterized by astrogliosis as seen by the hypertrophied and enlarged processes of several astrocytes (GFAP in green) and profound increase and redistribution of ADK immunoreactivity (in red).Scale bar: 5µm.
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