Inosine, Guanosine and Uridine as Promising Antiepileptic Drugs

What is it about?

Adenosine (Ado) and some non-adenosine (non-Ado) nucleosides including inosine (Ino), guanosine (Guo) and uridine (Urd) are modulatory molecules in the central nervous system (CNS), regulating different physiological and pathophysiological processes in the brain such as sleep and epilepsy. Indeed, different drugs effective on adenosinergic system (e.g., Ado metabolism inhibitors, agonists and antagonists of Ado receptors) are being used in drug development for the treatment of epileptic disorders. Although (i) endogenous Ino, Guo and Urd showed anticonvulsant/antiepileptic effects (e.g., in quinolinic acid - induced seizures and in different epilepsy models such as hippocampal kindling models), and (ii) there is need to generate new and more effective antiepileptic drugs for the treatment of drug-resistant epilepsies, our knowledge about antiepileptic influence of non-Ado nucleosides is far from complete. Thus, in this review article, we give a short summary of anticonvulsant/antiepileptic effects and mechanisms evoked by Ino, Guo, and Urd. Finally, we discuss some non-Ado nucleoside derivatives and their structures, which may be candidates as potential antiepileptic agents.

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Why is it important?

Non-Ado nucleosides and their analogues may enable us to decrease seizure/epileptic activity via endogenous mechanisms and, therefore, are promising therapeutic agents. In addition, application of Ino, Guo and Urd may allow us to increase the extracellular level of the endogenous antiepileptic Ado (as a special way of the Ado augmenting therapy) and its binding to Ado receptors by decreasing Ado uptake via nucleoside transporters because non-Ado nucleosides and Ado may compete for nucleoside transporters. Therapeutic application of Ado and its analogues may cause side effects, whereas increase of extracellular level of endogenous Ado by non-Ado nucleosides may be safer and more effective therapeutic approaches. Indeed, Ino, Guo, Urd and their analogues may be useful, effective and safe antiepileptic drugs without severe adverse effects: these nucleosides are well tolerated, safe drugs with only minor side effects. Consequently, although (i) Ino, Guo, and Urd binding sites (Ado receptors, GABAA receptors and/or their own specific Ino, Guo, or Urd receptors), (ii) brain areas and neuronal types expressing non-Ado nucleoside binding sites, (iii) cell-type/brain area specific effects of non-Ado nucleosides, (iv) exact interaction of Ino, Guo and Urd with other neurotransmitter systems (such as Guo and glutamatergic system) and (v) modulators as well as exact signaling mechanisms induced by Ino, Guo and Urd are not disclosed, a great deal of evidence suggests that non-Ado nucleosides (alone or in combination) may also be potential therapeutic agents in treatment of drug refractory epilepsy.

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