Role of adenosine in status epilepticus: a potential new target?

The homeostatic bioenergetic network regulator adenosine is an endogenous anticonvulsant of the brain that plays critical roles in seizure termination and postictal refractoriness. Adenosine homeostasis in the adult brain is largely under the control of metabolic clearance through adenosine kinase (ADK), expressed predominantly in astrocytes. The role of adenosine in status epilepticus (SE) appears to be a double-edged sword. We demonstrated that the severity of an SE clearly depends on the expression levels of ADK. A genetic knockdown of ADK prevented SE in a mouse model, whereas transgenic overexpression of the enzyme aggravated the SE. Therefore, ADK inhibition or adenosine augmentation might be a therapeutic strategy to terminate or attenuate an SE. On the other hand, SE triggers a surge of endogenous adenosine, which may initiate secondary events leading to epileptogenesis. Two new findings point into this direction: (1) Elevated adenosine triggers changes in the epigenome; and (2) SE triggers transient changes in ADK expression, which have been linked to neurogenesis. Although the ADK/adenosine system is an attractive target for the attenuation of an SE, the same system may also trigger downstream events related to epileptogenesis.