The Antiepileptic Potential of Nucleosides

Abstract

Despite newly developed antiepileptic drugs to suppress epileptic symptoms, approximately one third of patients remain drug refractory. Consequently, there is an urgent need to develop more effective therapeutic approaches to treat epilepsy. A great deal of evidence suggests that endogenous nucleosides, such as adenosine (Ado), guanosine (Guo), inosine (Ino) and uridine (Urd), participate in the regulation of pathomechanisms of epilepsy. Adenosine and its analogues, together with non-adenosine (non-Ado) nucleosides (e.g., Guo, Ino and Urd), have shown antiseizure activity. Adenosine kinase (ADK) inhibitors, Ado uptake inhibitors and Ado-releasing implants also have beneficial effects on epileptic seizures. These results suggest that nucleosides and their analogues, in addition to other modulators of the nucleoside system, could provide a new opportunity for the treatment of different types of epilepsies. Therefore, the aim of this review article is to summarize our present knowledge about the nucleoside system as a promising target in the treatment of epilepsy.

Absence epileptic activity changing effects of non-adenosine nucleoside inosine, guanosine and uridine in Wistar Albino Glaxo Rijswijk rats

“…Increased expression of excitatory A 2A receptors was demonstrated not only in thalamic brain areas but also in the trigger zone of absence epileptic activity (somatosensory cortex) of symptomatic WAG/Rij rats (D'Alimonte et al, 2009). Thus, in accordance with cortical focus theory of absence epilepsy (Coenen and Van Luijtelaar, 2003;Depaulis and Van Luijtelaar, 2005;Lu¨ttjohann et al, 2011), an increased number of A 2A receptors may evoke/increase excitation in the somatosensory cortex by facilitation of glutamate release/glutamatergic system in WAG/Rij rats, which may trigger/propagate the absence epileptic activity (D'Alimonte et al, 2009;Kova´cs et al, 2014). This hypothesis was strengthened by observations that the i.p.…”

“…Indeed, adenosine (Ado) and non-adenosine (non-Ado) nucleosides (e.g., inosine/Ino, guanosine/Guo and uridine/Urd) have a role in the regulation of physiological and pathophysiological processes in the brain, such as the regulation of sleep and memory, Parkinson's disease, Alzheimer's disease and epilepsy (Burnstock et al, 2011;Kova´cs and Dobolyi, 2013;Kova´cs et al, 2014). Therefore, several nucleoside uptake inhibitors, nucleoside metabolic inhibitors and nucleoside derivatives are being used in drug development for the treatment of different CNS diseases (Boison, 2011;Kova´cs and Dobolyi, 2013;Kova´cs et al, 2014).…”

“…Indeed, adenosine (Ado) and non-adenosine (non-Ado) nucleosides (e.g., inosine/Ino, guanosine/Guo and uridine/Urd) have a role in the regulation of physiological and pathophysiological processes in the brain, such as the regulation of sleep and memory, Parkinson's disease, Alzheimer's disease and epilepsy (Burnstock et al, 2011;Kova´cs and Dobolyi, 2013;Kova´cs et al, 2014). Therefore, several nucleoside uptake inhibitors, nucleoside metabolic inhibitors and nucleoside derivatives are being used in drug development for the treatment of different CNS diseases (Boison, 2011;Kova´cs and Dobolyi, 2013;Kova´cs et al, 2014). Non-Ado nucleoside Ino, Guo and Urd may enter the brain via the blood-brain barrier (Lewin and Bleck, 1985;Sle´zia et al, 2004;Soares et al, 2004;Cansev, 2006;Ipata, 2011) and are also derived from intracellular and/or extracellular metabolism of nucleotides by nucleotidases in the brain (Ipata, 2011;Kova´cs et al, 2013a;Ipata and Balestri, 2014).…”

“…Antiepileptic effects of Ado and Ado receptor agonists as well as antagonists are extensively investigated but our knowledge relating to effect of non-Ado nucleosides on epileptic activity is far from complete (Boison, 2011;Masino et al, 2012;Kova´cs et al, 2014Kova´cs et al, , 2015. For instance, it was revealed that (i) Ino showed an anticonvulsant effect on quinolinic acid (QA)-induced seizures (Ganzella et al, 2011), (ii) Guo may decrease QAinduced seizures dose-dependently (Schmidt et al, 2000) and (iii) Urd decreased epileptic activity in the rat hippocampal kindling model (Zhao et al, 2008) and in a model of human absence epilepsy Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats (Kova´cs et al, 2013b) suggesting the antiepileptic potential of non-Ado nucleosides.…”

Lipopolysaccharide induced increase in seizure activity in two animal models of absence epilepsy WAG/Rij and GAERS rats and Long Evans rats

“…There are also similarities with some differences between the 3 strains as far as the mechanisms of SWDs. It has been demonstrated, that (i) several neurotransmitter systems are involved in the pathophysiological processes leading to absence epileptic seizures and their maintenance/recurrence such as glutamatergic system, GABAergic system, dopaminergic and nucleosiderg system in GAERS rats, WAG/Rij rats and Long Evans rats (Bazyan and Van Luijtelaar, 2013;Depaulis and Van Luijtelaar, 2005;Kovács et al, 2013Kovács et al, , 2014Li et al, 2006;Polack and Charpier, 2006), (ii) the effects of anti-epileptic drugs on SWDs were similar in GAERS rats, WAG/Rij rats and Long Evans rats (e.g., ethosuximide, and valproate decreased the number of SWDs) (Chen et al, 2011;Depaulis and Van Luijtelaar, 2005;Shaw, 2004Shaw, , 2007, (iii) sodium channel (Nav1.1 and Nav1.6) expression was selectively increased in the somatosensory cortex of WAG/Rij rats in relation to age-dependent increase in seizure number and duration (Klein et al, 2004), (iv) selective decrease in thalamic (e.g., reticular thalamic nucleus) and cortical (e.g., somatosensory cortex) GABA (A) receptor subunits such as reduction of ␣3 subunit of GABA (A) receptor in reticular thalamic nucleus of WAG/Rij rats (Liu et al, 2007) may have a role in the pathophysiology of absence epilepsy in Long Evans rats, WAG/Rij rats and GAERS rats (Li et al, 2006;Spreafico et al, 1993), (v) mRNA levels for most GABA (B(1)) subunits were lower in WAG/Rij neocortex than in cortex of control nonepileptic rats, which can contribute to neocortical hyperexcitability and SWD generation (Merlo et al, 2007) whereas GABA (B(1)) subunit mRNA levels were higher and lower in the somatosensory cortex and ventrobasal thalamic nuclei of GAERS rats, respectively, compared with control animals (Princivalle et al, 2003), (vi) decreased alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid receptor (AMPA; AMPA-GluR4) and N-methyl-d-aspartate receptor (NMDA; NMDA-NR1) expression in the cortical focus of WAG/Rij animals (compared with non-epileptic control rats) and increased AMPA-GluR1/2 expression in GAERS rats in the somatosensory cortex may be in relation to hyperexcitability in somatosensory cortex and to SWD initiation (Van de BovenkampJanssen et al, 2006;Kennard et al, 2011), (vii) reduction of group-I metabotropic glutamate receptors (mGlu1 receptors) in ventrobasal thalamic nuclei and increased expression of group-II metabotropic glutamate receptors (mGlu2/3 receptors) in WAG/Rij rat somatosensory cortex and ventrobasal thalamic nuclei may be involved in the ge...…”