Effects of Levetiracetam in Acute and Kindling Model of Epilepsy Through Adenosinergic Pathway in Mice: Possible Involvement of Adenosine A1 Receptor

Objective: The present study aimed to explore the possible levetiracetam mechanisms of action in the adenosine signaling systems using the PTZ-induced acute seizure and the PTZ-induced kindling model of epileptogenesis.Method: In acute model, male mice received caffeine (non-specific adenosine receptor antagonist), or dipropylcyclopentylxanthine (DPCPX) (specific A1 receptor antagonist) prior to levetiracetam. After 30 minutes, a convulsant dose of PTZ (100 mg/kg) was administered to determine whether caffeine or DPCPX have any antagonistic effects on anti-seizure activity of levetiracetam by analyzing the onset of first myoclonic jerk (FMJ), generalized clonic seizures (GCS) and percent mortality.The chronic PTZ-induced kindling model was set to assess the gene expression changes in adenosine A1 receptor, inwardly-rectifying potassium channel (Kir3.2) and equilibrative nucleoside transporter-1 (ENT-1) through RT-qPCR. Data were analyzed using Origin statistical software version 8.5 and represented as Mean ± SEM.Results: In acute study, we found that caffeine (100 mg/kg) and DPCPX (25 mg/kg) reversed the anti-seizures effects of the levetiracetam significantly by reversing the percent protection and shortening the delay in the FMJ and onset of GCS in animals. In kindling model of epileptogenesis, it was found that levetiracetam increased the gene expression of adenosine A1 receptor andKir3.2 in the brain. Furthermore, levetiracetam significantly reduced the gene expression of ENT-1 in the brain that supposed to enhance the extracellular adenosine in the brain.Conclusion: Based on these results, it can be concluded that in addition to its action on SV2A vesicular protein, levetiracetam also prevent epileptogenesis by acting on the adenosine pathway in the CNS.