One-third of epileptic patients are drug refractory due to the limited efficacy of antiepileptic
therapy. Thus, there is an immense need to find more effective, safer and well-tolerated antiepileptic
drugs. A great deal of results suggests that adenosine (Ado), guanosine (Guo), inosine (Ino) or uridine
(Urd) are endogenous antiepileptogenic modulators. Furthermore, nucleosides and their derivatives may be safe and effective
potential drugs in the treatment of epilepsy. Conversely, nucleosidergic modulatory system implying nucleoside levels,
metabolism, receptors and transporters may also be involved in seizure pathomechanisms. Application of Ado receptor
agonists as well as antagonists, elevation of nucleoside levels (e.g., by nucleoside metabolism inhibitors, and Adoreleasing
implants) or utilization of non-Ado nucleosides may also turn to be useful approaches to decrease epileptic activity.
However, all drugs exerting their effects on the nucleosidergic modulatory system may affect the fine regulation of
glia-neuron interactions that are intimately governed by various nucleosidergic processes. Perturbation of the complex,
bidirectional communication between neurons and astrocytes through these nucleosidergic modulatory mechanisms may
lead to pathological changes in the central nervous system (CNS) and therefore may cause significant side effects. Thus, a
deeper understanding of the nucleosidergic modulatory control over glia-neuron interactions is essential in order to develop
more effective and safe nucleoside-based antiepileptic drugs. In this review article we focus on the role of Ado and
Urd in glia-neuron interactions, placing emphasis on their implications for the treatment of epilepsy.