Abstracts

Rationale: Due to the limited efficacy and side effects of current antiepileptic drugs (AEDs), the search for new therapeutic agents is critical. Uridine, a possible endogenous antiepileptic modulator, has been demonstrated to have anticonvulsant effects in some models of epilepsy, but not others. In our previous rapid kindling study, the kindling rate was slower and the afterdischarges (AD) duration were shorter in the uridine-treated group than the controls, although the results did not reach statistical significance. In this study, we continued that work and studied traditional hippocampal kindling acquisition using daily stimulations during uridine administration. To optimize the result we used a higher dose (200 mg/kg) of uridine, normal saline (NS) as negative control and levetiracetam (LEV) as a positive control.Methods: Male adult Sprague Dawley rats (n=48) with jugular vein cannulation in place were used. A stimulating electrode was implanted in the left CA1 region and a recording bipolar electrode was put in the right CA1. Rats received daily electrical stimulus train (20 Hz; 2 sec) with suprathreshold current untill they had two consecutive stage 5 seizures. During the kindling process, we divided rats into four groups: IV uridine (200 mg/kg; n=12) once a day (UX1); uridine (200 mg/kg; n=12) three times a day (UX3); NS (n=12) once a day; LEV (54mg/kg; n=12) once a day. Seizure stages and AD durations were recorded daily.Results: Uridine and LEV were well tolerated by the rats with none of the animals demonstrating any signs of toxicity. There are significant differences between the four groups in number of stimulations to reach kindling stage 4 (NS 24.6±2.5; UX1 29.9±4.3; UX3 39.4±1.6; LEV 42.1±2.2, p < 0.0001) and stage 5 (NS 41.0±2.6; UX1 42.2±4.3; UX3 45.2±1.7; LEV 51.4±1.6, p < 0.05) with both the UX3 and LEV groups kindling slower than the NS controls (p < 0.05). Mean AD durations were shorter in the uridine and LEV treated groups than the NS controls (NS 50.1±4.9; UX1 35.1±3.0; UX3 37.7±2.6; LEV 35.5±1.6, p = 0.03)Conclusions: CONCLUSION: These results confirm that uridine has antiepileptogenic properties in the kindling model. Furthermore the antiepileptogenic effects of uridine were similar to those seen with LEV. Clinical trials of uridine in epilepsy are now warranted. (Funding supported by: RepliGen Corporation)