Uric acid and allopurinol aggravate absence epileptic activity in Wistar Albino Glaxo Rijswijk rats.

Uric acid has a role in several physiological and pathophysiological processes. For example, uric acid may facilitate seizure generalization while reducing uric acid level may evoke anticonvulsant/antiepileptic effects. Allopurinol blocks the activity of xanthine oxidase, by which allopurinol inhibits catabolism of hypoxanthine to xanthine and uric acid and, as a consequence, decreases the level of uric acid. Although the modulation of serum uric acid level is a widely used strategy in the treatment of certain diseases, our knowledge regarding the effects of uric acid on epileptic activity is far from complete. Thus, the main aim of this study was the investigation of the effect of uric acid on absence epileptic seizures (spike-wave discharges: SWDs) in a model of human absence epilepsy, the Wistar Albino Glaxo/Rijswijk (WAG/Rij) rat. We investigated the influence of intraperitoneally (i.p.) injected uric acid (100 mg/kg and 200 mg/kg), allopurinol (50 mg/kg and 100 mg/kg), a cyclooxygenase 1 and 2 (COX-1 and COX-2) inhibitor indomethacin (10 mg/kg) and inosine (500 mg/kg) alone and the combined application of allopurinol (50 mg/kg) with uric acid (100 mg/kg) or inosine (500 mg/kg) as well as indomethacin (10 mg/kg) with uric acid (100 mg/kg) and inosine (500 mg/kg) with uric acid (100 mg/kg) on absence epileptic activity. We demonstrated that both uric acid and allopurinol alone significantly increased the number of SWDs whereas indomethacin abolished the uric acid-evoked increase in SWD number. Our results suggest that uric acid and allopurinol have proepileptic effects in WAG/Rij rats.

Absence epileptic activity in Wistar Albino Glaxo Rijswijk rat mothers.

Absence epileptic activity was analyzed during pregnancy, the postpartum period and after weaning to establish alterations of seizures throughout the reproductive cycle. Wistar Albino Glaxo Rijswijk (WAG/Rij) rats were used in the study as a model of absence epilepsy and because their seizures do not interfere with rearing offspring. The number of spike-wave discharges (SWDs) was gradually elevated from the 19th pregnancy day to delivery. Meanwhile, the characteristics of individual SWDs did not change suggesting that SWD generation remained the same. In the postpartum and postweaning periods, the number of SWDs was not increased in the absence of pups. However, returning the pups to mothers resulted in a markedly elevated number of SWDs for 1h. If pups were taken away after 30min, the number of SWDs dropped immediately suggesting that the presence of pups increased the SWD number. The time mothers spent with the litter and in kyphosis suckling posture were in correlation with their SWD number further suggesting the importance of interaction with pups in SWD induction. Suckling elevates prolactin levels but surprisingly, its intracerebroventricular injection markedly reduced SWD number in suckled WAG/Rij mothers suggesting that the SWD-inducing effect of suckling is not mediated by prolactin. Rather, the elevated prolactin level may provide some protection against pro-epileptic effects of suckling. In conclusion, we first identified periods within the reproductive cycle with increased absence epileptic activity, implying that more attention should be devoted to epileptic activity changes in mothers.

Guanosine may increase absence epileptic activity by means of A2A adenosine receptors in Wistar Albino Glaxo Rijswijk rats.

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 50mg/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 (20mg/kg Guo) and 3rd as well as 4th (50mg/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. 50mg/kg Guo decreased but, surprisingly, i.p. 100mg/kg Guo enhanced the number of SWDs in WAG/Rij rats. Combined i.p. injection of a non-selective Ado receptor antagonist theophylline (5mg/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) (1mg/kg) and a cyclooxygenase 1 and 2/COX-1 and COX-2 inhibitor indomethacin (10mg/kg) with 100mg/kg Guo decreased the SWD number compared to i.p. 100mg/kg Guo alone. The results suggest that i.p. 100mg/kg Guo can increase SWD number by means of the adenosinergic system.