Guanosine may increase absence epileptic activity by means of A2A adenosine receptors

What is it about?

The non-adenosine nucleoside guanosine (Guo) was demonstrated to decrease quinolinic acid(QA)-induced seizures, spontaneously emerged absence epileptic seizures and lipopolysaccharide(LPS)-evoked induction of absence epileptic seizures suggesting its antiepileptic potential. It was also described previously that intraperitoneal (i.p.) injection of 20 and 50 mg/kg Guo decreased the number of spike-wave discharges (SWDs) in a well investigated model of human absence epilepsy, the Wistar Albino Glaxo Rijswijk (WAG/Rij) rats during 4th (20 mg/kg Guo) and 3rd as well as 4th (50 mg/kg Guo) measuring hours. Guanosine can potentially decrease SWD number by means of its putative receptors but absence epileptic activity changing effects of Guo by means of increased extracellular adenosine (Ado) cannot be excluded. An increase in the dose of i.p. injected Guo is limited by its low solubility in saline, therefore, we addressed in the present study whether higher doses of Guo, diluted in sodium hydroxide (NaOH) solution, have more potent antiepileptic effect in WAG/Rij rats. We confirmed that i.p. 50 mg/kg Guo decreased but, surprisingly, i.p. 100 mg/kg Guo enhanced the number of SWDs in WAG/Rij rats. Combined i.p. injection of a non-selective Ado receptor antagonist theophylline (5 mg/kg) or a selective Ado A2A receptor (A2AR) antagonist SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) (1 mg/kg) and a cyclooxygenase 1 and 2/COX-1 and COX-2 inhibitor indomethacin (10 mg/kg) with 100 mg/kg Guo decreased the SWD number compared to i.p. 100 mg/kg Guo alone.

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Why is it important?

Lower Guo doses, such as i.p. 20 and 50 mg/kg have alleviating effects on SWD number whereas higher doses of Guo (e.g., i.p. 100 mg/kg) may augment absence epileptic activity by means of Ado/A2AR/COX/PGE2 system in WAG/Rij rats. Moreover, the Ado/A2AR/COX/PGE2 system also may have a role in neuroinflammation- and age-evoked increase in SWD number.

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