Modulation of adenosinergic system and its application for the treatment of epilepsy

Adenosine is present in all cells and is implicated in the control of the function of every tissue and organ. The elevated adenosine levels seem to play a significant role in a protection against cellular damage in the regions with increased metabolic demand and prevent the subsequent dysfunction of the affected organs. Furthermore, adenosine has been shown to play an important role not only in the regulation of pathophysiological processes, but also in the modulation of normal physiological processes, for example, the regulation of sleep and arousal as well as by impact on pre- or postsynaptic receptors involved in releasing neurotransmitters (e.g. glutamate, acetylcholine, norepinephrine, 5-hydroxytryptamine, dopamine, GABA and others). Experimental studies provide evidence supporting the role of adenosine as an endogenous anticonvulsant agent. Numerous adenosine agonists acting through A1, A2 and A3 receptors were proven as potent anticonvulsant compounds in a wide variety of animal models of epilepsy. However, despite their efficacy in such models, adenosine receptor agonists do not appear to be good candidates for successful clinical applications. The therapeutic range of systemically administered adenosine receptor agonists is very narrow and they often produce profound adverse events. It seems, therefore, that adenosine receptor agonists could only be used clinically when co-administered with other antiepileptic drugs or when used in local therapies, where their side effect profile is much more tolerable. An alternative strategy would be to enhance the natural adenosinergic feedback mechanism triggered by seizures by using adenosine uptake inhibitors. This approach seems very attractive as it would allow limiting the action only in the active areas such as seizure foci and thus, preventing the systemic side effects.